ACE2

Summary

ACE2 (angiotensin converting enzyme 2, HGNC:13557) is a protein-coding gene on chromosome Xp22.2, encoding Angiotensin-converting enzyme 2 (Q9BYF1). Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis.

The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. ACE2 is known to be expressed in various human organs, and its organ- and cell-specific expression suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2, the latter is the causative agent of coronavirus disease-2019 (COVID-19). Multiple splice variants have been found for this gene and the dACE2 (or MIRb-ACE2) splice variant has been found to be interferon inducible.

Source: NCBI Gene 59272 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 329 total — 52 pathogenic, 2 likely-pathogenic
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001371415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13557
Approved symbol	ACE2
Name	angiotensin converting enzyme 2
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	ACEH
Ensembl gene	ENSG00000130234
Ensembl biotype	protein_coding
OMIM	300335
Entrez	59272

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000252519, ENST00000427411, ENST00000471548, ENST00000473851, ENST00000677282, ENST00000678046, ENST00000678073, ENST00000679162, ENST00000679212, ENST00000679278, ENST00000680121, ENST00000871928, ENST00000871929, ENST00000871930, ENST00000871931, ENST00000954330, ENST00000954331

RefSeq mRNA: 6 — MANE Select: NM_001371415 NM_001371415, NM_001386259, NM_001386260, NM_001388452, NM_001389402, NM_021804

CCDS: CCDS14169, CCDS94556, CCDS94557

Canonical transcript exons

ENST00000252519 — 18 exons

Exon	Start	End
ENSE00000894057	15594845	15595003
ENSE00000894058	15592229	15592322
ENSE00000894059	15591713	15591856
ENSE00000894060	15589344	15589456
ENSE00000894061	15587753	15587858
ENSE00000894062	15585475	15585572
ENSE00000894063	15581221	15581390
ENSE00000894064	15578089	15578315
ENSE00000894065	15575666	15575810
ENSE00000894066	15573367	15573465
ENSE00000894067	15572201	15572323
ENSE00000894068	15571624	15571796
ENSE00000894069	15570295	15570353
ENSE00000894070	15567726	15567826
ENSE00000894071	15566253	15566369
ENSE00001334055	15561033	15562013
ENSE00003507229	15564024	15564218
ENSE00003897519	15600726	15600960

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 97.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8600 / max 428.0835, expressed in 83 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198534	0.4401	45
198535	0.3524	47
198536	0.0585	23
209610	0.0090	5

Top tissues by expression

255 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.73	gold quality
ileum	UBERON:0002116	97.66	silver quality
gall bladder	UBERON:0002110	96.47	gold quality
jejunal mucosa	UBERON:0000399	95.23	gold quality
duodenum	UBERON:0002114	92.36	gold quality
right testis	UBERON:0004534	91.15	gold quality
left testis	UBERON:0004533	89.63	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.13	gold quality
testis	UBERON:0000473	85.60	gold quality
small intestine	UBERON:0002108	85.14	gold quality
heart left ventricle	UBERON:0002084	83.12	gold quality
adult mammalian kidney	UBERON:0000082	82.25	gold quality
cardiac ventricle	UBERON:0002082	81.69	gold quality
mucosa of transverse colon	UBERON:0004991	81.24	gold quality
apex of heart	UBERON:0002098	80.41	gold quality
right atrium auricular region	UBERON:0006631	78.93	gold quality
kidney epithelium	UBERON:0004819	78.37	silver quality
heart	UBERON:0000948	77.34	gold quality
cardiac atrium	UBERON:0002081	76.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.69	gold quality
pancreatic ductal cell	CL:0002079	76.58	gold quality
buccal mucosa cell	CL:0002336	76.51	gold quality
kidney	UBERON:0002113	76.33	gold quality
omental fat pad	UBERON:0010414	76.21	gold quality
rectum	UBERON:0001052	76.17	gold quality
peritoneum	UBERON:0002358	76.12	gold quality
adipose tissue of abdominal region	UBERON:0007808	74.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.45	gold quality
transverse colon	UBERON:0001157	72.33	gold quality
cortex of kidney	UBERON:0001225	71.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, HIF1A, HNF1A, HNF1B, MTF2, SRY

Literature-anchored findings (GeneRIF, showing 40)

• role in hydrolyzing biological peptides (PMID:11815627)
• tissue distribution of ACE 2 mRNA by RT-PCR (PMID:12459472)
• We tested the hypothesis that cardiac ACE2 activity contributes to features of ventricular remodeling associated with the renin-angiotensin system (PMID:12967627)
• ACE2 is a functional receptor for the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). (PMID:14647384)
• a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein; ACE2 is a functional receptor for SARS-CoV (PMID:14647384)
• ACE2 binds to a 193-amino acid fragment of the SARS coronavirus S protein (PMID:14670965)
• large hinge-bending motion is important for inhibitor binding and catalysis in ACE2 (PMID:14754895)
• ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts–REVIEW (PMID:15165741)
• ACE2 is a constitutive product of adult-type Leydig cells and may participate in the control of testicular function by as yet unknown mechanisms. (PMID:15231706)
• Angiotensin-converting enzyme 2 gene (ACE2) is little associated in genetic predisposition to hypertension. (PMID:15233982)
• We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). (PMID:15283675)
• Failure of angiotensin-(1-9) to increase in response to increased angiotensin I indicated little role for ACE2 in angiotensin I metabolism. Levels of angiotensin-(1-7) were more linked to those of angiotensin I than angiotensin II. (PMID:15361769)
• cloning and characterization of a constitutively secreted form of ACE2 (PMID:15380922)
• This article will focus on angiotensin-converting enzyme 2 (ACE2) as a new, potential target of gene therapy for hypertensive disorders. (PMID:15640278)
• Upregulated in nonischemic but not ischemic cardiomyopathy. (PMID:15769906)
• Results identify the SARS coronavirus spike protein binding site on angiotensin-converting enzyme 2. (PMID:15791205)
• A molecular docking model of SARS-CoV S1 protein in complex with human ACE2 was constructed and the interacting residue pairs within this complex model and their contact types are described. (PMID:15979045)
• ADAM17 is the protease responsible for shedding of the SARS-CoV receptor, ACE2 (PMID:15983030)
• data identify a critical function for ACE2 in acute lung injury (PMID:16001071)
• report associates severe congenital uropathies and renal hypodysplasia with decreased renin-angiotensin system activity associated with the ACE II genotype and a possible functional imbalance among ATR1 receptors. (PMID:16006956)
• This paper reviews data regarding the biochemistry of angiotensin-(1-7)-forming enzymes and the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1-7) in the control of the circulation. (PMID:16055515)
• Aortic distensibility was increased by prolonged training in endurance athletes, particularly in those with the ACE II genotype. This effect represents an extracardiac adaptation to chronic prolonged training in athletes. (PMID:16088128)
• ACE2 and ACE are ectoenzymes that have distinct localization and secretion patterns that determine their role on the cell surface in kidney epithelium (PMID:16166094)
• crystal structure at 2.9 angstrom resolution of the receptor-binding domain(RBD)of SARS coronavirus spike protein bound to the peptidase domain of ACE2 shows that the RBD presents a gently concave surface which cradles the N-terminal lobe of the peptidase (PMID:16166518)
• In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. (PMID:16211375)
• The G8790A polymorphism in angiotensin I converting enzyme 2 gene may be related to the essential hypertension with cardiac incompetence in Chinese population. (PMID:16215952)
• ACE2 might be involved in the progression of pulmonary sarcoidosis which may depend on gender. (PMID:16315782)
• ACE2 is expressed in the invading and intravascular trophoblast and in decidual cells during pregnancy. (PMID:16338465)
• ACE2 A/G polymorphism is associated with hypertension in patients with metabolic syndrome (PMID:16459167)
• charged amino acids between residues 22 and 57 were important (K26 and D30, in particular) as determinants on ACE2 critical for SARS-CoV infection (PMID:16510163)
• Telmisartan up-regulates the protein and gene expression of ACE2 in HUVECs in a concentration and time dependent manner. (PMID:16647014)
• shown to be localized on the apical plasma membrane of polarized respiratory epithelial cells and to mediate SARS-CoV infection from the apical side of these cells. (PMID:16690935)
• functions as a receptor for hCOV NL63 and 229E S proteins but is engaged diferentially by each strain. (PMID:16912312)
• There was higher angiotensin-converting enzyme (ACE) and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in ACE2 expression were detected. (PMID:16962475)
• analysis of SARS coronavirus interactions with ACE2 (PMID:17037534)
• analysis of spike protein of human coronavirus NL63 interaction with its cellular receptor ACE2 (PMID:17037543)
• ACE2 is a receptor for human respiratory coronavirus NL63 (PMID:17037544)
• SARS coronavirus airway epithelial infection is associated with ACE2 expression and localization (review) (PMID:17037581)
• Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. (PMID:17079315)
• ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension (PMID:17303661)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ace2	ENSDARG00000016918
mus_musculus	Ace2	ENSMUSG00000015405
rattus_norvegicus	Ace2	ENSRNOG00000031665
caenorhabditis_elegans		WBGENE00000039

Paralogs (1): ACE (ENSG00000159640)

Protein

Protein identifiers

Angiotensin-converting enzyme 2 — Q9BYF1 (reviewed: Q9BYF1)

Alternative names: Angiotensin-converting enzyme homolog, Angiotensin-converting enzyme-related carboxypeptidase, Metalloprotease MPROT15

All UniProt accessions (6): Q9BYF1, A0A7I2V2E9, A0A7I2V3N4, A0A7I2V3X6, A0A7I2V4H0, A0A7I2V5W5

UniProt curated annotations — full annotation on UniProt →

Function. Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins (apelin-13, [Pyr1]apelin-13, apelin-17, apelin-36), casomorphins (beta-casomorphin-7, neocasomorphin) and dynorphin A with high efficiency. In addition, ACE2 C-terminus is homologous to collectrin and is responsible for the trafficking of the neutral amino acid transporter SL6A19 to the plasma membrane of gut epithelial cells via direct interaction, regulating its expression on the cell surface and its catalytic activity. (Microbial infection) Acts as a receptor for human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63. Non-functional as a carboxypeptidase. (Microbial infection) Non-functional as a receptor for human coronavirus SARS-CoV-2.

Subunit / interactions. Homodimer. Interacts with the catalytically active form of TMPRSS2. Interacts with SLC6A19; this interaction is essential for expression and function of SLC6A19 in intestine. Interacts with ITGA5:ITGB1. Probably interacts (via endocytic sorting signal motif) with AP2M1; the interaction is inhibited by phosphorylation of Tyr-781. Interacts (via PDZ-binding motif) with NHERF1 (via PDZ domains); the interaction may enhance ACE2 membrane residence. (Microbial infection) Interacts with SARS coronavirus/SARS-CoV spike protein. (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein (via RBD domain). (Microbial infection) Interacts with human coronavirus NL63 spike protein. (Microbial infection) Interacts with human coronavirus NL63/HCoV-NL63 spike glycoprotein. (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein; the interaction is increased by AVP/Arg-vasopressin with which they may form a complex.

Subcellular location. Secreted Cell membrane. Cytoplasm. Cell projection. Cilium. Apical cell membrane Apical cell membrane.

Tissue specificity. Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells (at protein level). Expressed in enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level). Expressed in the renal proximal tubule and the small intestine (at protein level). Expressed in heart, kidney, testis, and gastrointestinal system (at protein level). In lung, expressed at low levels in some alveolar type 2 cells, the expression seems to be individual-specific (at protein level). Expressed in nasal epithelial cells (at protein level). Coexpressed with TMPRSS2 within some lung alveolar type 2 cells, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells. Coexpressed with TMPRSS4 within mature enterocytes. Expressed in nasal and bronchial epithelial cells (at protein level).

Post-translational modifications. N-glycosylation on Asn-90 may limit SARS infectivity. Proteolytic cleavage by ADAM17 generates a secreted form. Also cleaved by serine proteases: TMPRSS2, TMPRSS11D and HPN/TMPRSS1. Phosphorylated. Phosphorylation at Tyr-781 probably inhibits interaction with AP2M1 and enables interactions with proteins containing SH2 domains. Ubiquitinated. Ubiquitinated on Lys-788 via ‘Lys-48’-linked ubiquitin. ‘Lys-48’-linked deubiquitinated by USP50 on the Lys-788; leading to its stabilization.

Activity regulation. Regulated by chloride and fluoride, but not bromide. Chloride increases angiotensin I and decreases angiotensin II cleavage. Inhibited by MLN-4760, cFP_Leu, and EDTA, but not by the ACE inhibitors lisinopril, captopril and enalaprilat. Highly potent and selective in vitro ACE2 inhibitors were identified.

Cofactor. Binds 1 zinc ion per subunit. Binds 1 Cl(-) ion per subunit.

Domain organisation. The extracellular region of the ACE2 enzyme is composed of two domains. The first is a zinc metallopeptidase domain (residues 19-611). The second domain is located at the C-terminus (residues 612-740) and is 48% identical to human collectrin. The cytoplasmic tail contains several linear motifs such as LIR, PDZ-binding, PTB and endocytic sorting signal motifs that would allow interaction with proteins that mediate endocytic trafficking and autophagy.

Induction. Up-regulated in failing heart. Expression is induced by IFNA and IFNG. Exposure to cigarette smoke increases expression in lungs. Expression is decreased in nasal and bronchial epithelium of individuals with allergy after allergen challenge. IL13 stimulation decreases expression in nasal and bronchial epithelium. Not induced by interferons such as IFNA, IFNB and IFNG. Expression is induced by interferons such as IFNA, IFNB and IFNG. It seems that isoform 2 is an interferon-stimulated gene (ISG) but not isoform 1. (Microbial infection) In airway epithelial cells, expression is increased upon influenza A virus infection. (Microbial infection) In airway epithelial cells, expression is induced by viruses such rhinoviruses and influenza virus. (Microbial infection) Induced by human coronavirus SARS-CoV-2.

Similarity. Belongs to the peptidase M2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BYF1-1	1, long	yes
Q9BYF1-3	2, delta, dACE2, short

RefSeq proteins (6): NP_001358344, NP_001373188, NP_001373189, NP_001375381, NP_001376331, NP_068576 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001548	Peptidase_M2	Family
IPR031588	Collectrin_dom	Domain

Pfam: PF01401, PF16959

Enzyme classification (BRENDA):

• EC 3.4.15.1 — peptidyl-dipeptidase A (BRENDA: 31 organisms, 224 substrates, 941 inhibitors, 246 Km, 169 kcat entries)
• EC 3.4.17.23 — angiotensin-converting enzyme 2 (BRENDA: 30 organisms, 124 substrates, 241 inhibitors, 10 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

101 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HIPPURYL-HIS-LEU	0.0308–20	30
ANGIOTENSIN I	0.009–2.7	25
BENZYLOXYCARBONYL-PHE-HIS-LEU	0.13–2.8	8
BENZOYL-GLY-HIS-LEU	0.56–18.2	4
LEQIYHL	0.0157–0.4125	4
LVVYPWTQRY	0.014–0.033	4
N-(3-(2-FURYL)ACRYLOYL)-PHE-PHE-ARG	0.05–0.12	4
NKLKPSQWI	0.0147–0.5237	4
NKLKPSQWISL	0.0027–0.1505	4
NKLKPSQWISLSD	0.1367–0.6738	4
[PHE9,ARG10]ANGIOTENSIN I	0.011–0.025	4
ANGIOTENSIN II	0.005–0.0586	4
2-FURANACRYLOYL-PHE-GLY-GLY	0.08–0.174	3
HIPPURYL-PHE-ARG	0.5–1.8	3
N-(3-(2-FURYL)ACRYLOYL)-PHE-ALA-LYS	0.14–0.17	3

Catalyzed reactions (Rhea), 12 shown:

• angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine (RHEA:26554)
• angiotensin I + H2O = angiotensin-(1-9) + L-leucine (RHEA:63532)
• bradykinin(1-8) + H2O = bradykinin(1-7) + L-phenylalanine (RHEA:63536)
• neurotensin + H2O = neurotensin-(1-12) + L-leucine (RHEA:63540)
• kinetensin + H2O = kinetensin-(1-8) + L-leucine (RHEA:63544)
• dynorphin A-(1-13) + H2O = dynorphin A-(1-12) + L-lysine (RHEA:63556)
• apelin-13 + H2O = apelin-12 + L-phenylalanine (RHEA:63564)
• beta-casomorphin-7 + H2O = beta-casomorphin-6 + L-isoleucine (RHEA:63568)
• neurotensin-(1-8) + H2O = neurotensin-(1-7) + L-arginine (RHEA:63572)
• neocasomorphin + H2O = neocasomorphin-(1-5) + L-isoleucine (RHEA:63600)
• [Pyr1]apelin-13 + H2O = [Pyr1]apelin-12 + L-phenylalanine (RHEA:63604)
• apelin-17 + H2O = apelin-16 + L-phenylalanine (RHEA:63608)

UniProt features (193 total): mutagenesis site 67, helix 41, strand 24, turn 9, binding site 9, glycosylation site 7, region of interest 6, short sequence motif 5, sequence variant 4, sequence conflict 3, disulfide bond 3, chain 2, active site 2, topological domain 2, modified residue 2, domain 2, signal peptide 1, compositionally biased region 1, transmembrane region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

345 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9SPA	X-RAY DIFFRACTION	1.79
28KD	X-RAY DIFFRACTION	2.02
8BYJ	X-RAY DIFFRACTION	2.07
8B9P	X-RAY DIFFRACTION	2.11
8XSF	ELECTRON MICROSCOPY	2.16
1R42	X-RAY DIFFRACTION	2.2
7JVO	X-RAY DIFFRACTION	2.2
8TOR	X-RAY DIFFRACTION	2.2
9RVA	X-RAY DIFFRACTION	2.2
9UE7	ELECTRON MICROSCOPY	2.27
8TOQ	X-RAY DIFFRACTION	2.3
8BFW	X-RAY DIFFRACTION	2.33
8TOS	X-RAY DIFFRACTION	2.35
7UFK	X-RAY DIFFRACTION	2.38
9RVT	X-RAY DIFFRACTION	2.39
7EKH	X-RAY DIFFRACTION	2.4
6M0J	X-RAY DIFFRACTION	2.45
7T9K	ELECTRON MICROSCOPY	2.45
7LO4	X-RAY DIFFRACTION	2.46
8WE1	ELECTRON MICROSCOPY	2.47
7EFR	X-RAY DIFFRACTION	2.49
6LZG	X-RAY DIFFRACTION	2.5
9FMM	X-RAY DIFFRACTION	2.5
8DM5	ELECTRON MICROSCOPY	2.51
8VQR	X-RAY DIFFRACTION	2.56
7WPC	ELECTRON MICROSCOPY	2.57
7SY5	ELECTRON MICROSCOPY	2.59
7WHH	X-RAY DIFFRACTION	2.6
7SXZ	ELECTRON MICROSCOPY	2.61
7U0N	X-RAY DIFFRACTION	2.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYF1-F1	91.13	0.80

Antibody-complex structures (SAbDab): 19 — 7DX4, 7E7E, 7L0N, 7TN0, 7V61, 7XCP, 7YDI, 7YEG, 8DF5, 8E7M, 8FXB, 8FXC, 8S9G, 8WE4, 8XSF, 8XSJ, 8XXW, 8Y6A, 9R19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 375 (proton acceptor); 505 (proton donor)

Ligand- & substrate-binding residues (9): 169; 273; 345–346; 374; 378; 402; 477; 481; 515

Post-translational modifications (3): 781, 783, 788

Disulfide bonds (3): 133–141, 344–361, 530–542

Glycosylation sites (7): 53, 90, 103, 322, 432, 546, 690

Mutagenesis-validated functional residues (67):

Position	Phenotype
383	slightly inhibits interaction with sars-cov spike glycoprotein.
386	increases slightly the interaction with rbd domain of sars-cov-2 spike protein. in sace2.v2.2; increases interaction wit
389	slightly inhibits interaction with sars-cov spike glycoprotein.
389	increases very slightly the interaction with rbd domain of sars-cov-2 spike protein.
393	slightly inhibits interaction with sars-cov spike glycoprotein.
393	increases very slightly the interaction with rbd domain of sars-cov-2 spike protein.
425–427	slightly inhibits interaction with sars-cov spike glycoprotein.
465–467	no effect on interaction with sars-cov spike glycoprotein.
481	about 80% loss of angiotensin i cleavage.
505	complete loss of enzyme activity.
514	about 50% loss of angiotensin i cleavage but two-fold greater activity with angiotensin ii.
518	increases very slightly the interaction with rbd domain of sars-cov-2 spike protein.
559	slightly inhibits interaction with sars-cov spike glycoprotein.
603	no effect on interaction with sars-cov spike glycoprotein.
788	increases ace2 protein stability.
802–805	loss of interaction with nherf1.
19	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.
24–26	slightly inhibits interaction with sars-cov spike glycoprotein.
24	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.
25	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.
27	increases slightly the interaction with rbd domain of sars-cov-2 spike protein. in sace2.v2.2; increases interaction wit
29	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.
31	abolishes interaction with sars-cov spike glycoprotein.
31	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.
33	increases slightly the interaction with rbd domain of sars-cov-2 spike protein.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-9678110	Attachment and Entry
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9694614	Attachment and Entry
R-HSA-9733458	Induction of Cell-Cell Fusion
R-HSA-1643685	Disease
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-5663205	Infectious disease
R-HSA-9678108	SARS-CoV-1 Infection
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9772572	Early SARS-CoV-2 Infection Events
R-HSA-9772573	Late SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 268 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, TGACCTY_ERR1_Q2

GO Biological Process (28): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of cytokine production (GO:0001817), angiotensin maturation (GO:0002003), angiotensin-mediated drinking behavior (GO:0003051), regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081), tryptophan transport (GO:0015827), viral life cycle (GO:0019058), receptor-mediated endocytosis of virus by host cell (GO:0019065), regulation of vasoconstriction (GO:0019229), regulation of cell population proliferation (GO:0042127), symbiont entry into host cell (GO:0046718), receptor-mediated virion attachment to host cell (GO:0046813), negative regulation of smooth muscle cell proliferation (GO:0048662), regulation of inflammatory response (GO:0050727), positive regulation of amino acid transport (GO:0051957), maternal process involved in female pregnancy (GO:0060135), positive regulation of cardiac muscle contraction (GO:0060452), membrane fusion (GO:0061025), negative regulation of ERK1 and ERK2 cascade (GO:0070373), blood vessel diameter maintenance (GO:0097746), entry receptor-mediated virion attachment to host cell (GO:0098670), positive regulation of gap junction assembly (GO:1903598), regulation of cardiac conduction (GO:1903779), positive regulation of L-proline import across plasma membrane (GO:1905737), positive regulation of reactive oxygen species metabolic process (GO:2000379), proteolysis (GO:0006508), viral translation (GO:0019081), ceramide biosynthetic process (GO:0046513)

GO Molecular Function (13): virus receptor activity (GO:0001618), endopeptidase activity (GO:0004175), carboxypeptidase activity (GO:0004180), metallocarboxypeptidase activity (GO:0004181), metallopeptidase activity (GO:0008237), peptidyl-dipeptidase activity (GO:0008241), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), transporter activator activity (GO:0141109), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (14): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), cilium (GO:0005929), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), endocytic vesicle membrane (GO:0030666), brush border membrane (GO:0031526), membrane raft (GO:0045121), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
SARS-CoV Infections	3
SARS-CoV-2 Infection	2
Peptide hormone metabolism	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
Late SARS-CoV-2 Infection Events	1
Metabolism of proteins	1
Disease	1
Viral Infection Pathways	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
amino acid transport	2
symbiont entry into host cell	2
peptidase activity	2
exopeptidase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
regulation of angiotensin levels in blood	1
peptide hormone processing	1
brain renin-angiotensin system	1
drinking behavior	1
regulation of systemic arterial blood pressure by hormone	1
aromatic amino acid transport	1
viral process	1
receptor-mediated endocytosis	1
endocytosis involved in viral entry into host cell	1
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
cell population proliferation	1
regulation of cellular process	1
viral life cycle	1
symbiont entry into host	1
signaling receptor binding	1
virion attachment to host cell	1
negative regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
positive regulation of amine transport	1
regulation of amino acid transport	1
female pregnancy	1
multicellular organismal reproductive process	1
positive regulation of heart contraction	1

Protein interactions and networks

STRING

2768 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACE2	TMPRSS2	O15393	999
ACE2	SLC6A19	Q695T7	996
ACE2	AGTR1	P30556	996
ACE2	DPP4	P27487	995
ACE2	ERVW-1	Q9UQF0	994
ACE2	ERVFRD-1	P60508	992
ACE2	ERV3-1	Q14264	992
ACE2	AGT	P01019	989
ACE2	SLC6A20	Q9NP91	986
ACE2	CLEC4M	Q9H2X3	977
ACE2	BSG	P35613	968
ACE2	REN	P00797	960
ACE2	ACE	P12821	953
ACE2	AGTR2	P50052	953
ACE2	ANPEP	P15144	936

IntAct

579 interactions, top by confidence:

A	B	Type	Score
ACE2	S	psi-mi:“MI:0915”(physical association)	1.000
ACE2	S	psi-mi:“MI:0403”(colocalization)	1.000
ACE2	S	psi-mi:“MI:0407”(direct interaction)	1.000
S	ACE2	psi-mi:“MI:0407”(direct interaction)	1.000
S	ACE2	psi-mi:“MI:0915”(physical association)	1.000

BioGRID (2593): ACE2 (Affinity Capture-MS), CAT (Co-fractionation), ISYNA1 (Co-fractionation), ACE2 (Affinity Capture-MS), DLEU2 (Affinity Capture-RNA), ACE2 (Protein-RNA), ACE2 (Proximity Label-MS), S (Co-crystal Structure), ACE2 (Co-crystal Structure), SLC6A19 (Co-crystal Structure), SLC6A19 (Reconstituted Complex), ACE2 (Reconstituted Complex), ACE2 (Co-crystal Structure), ACE2 (Reconstituted Complex), ACE2 (Reconstituted Complex)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: D0G895, F1RRW5, P09470, P12820, P12821, P12822, P47820, Q10714, Q10715, Q10751, Q50JE5, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RFN1, Q6Q4G4, Q8R0I0, Q9BYF1, Q9GLN7, Q9VLJ6, Q0VCT4, Q9ESG3, Q9ESG4, Q9HBJ8

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
S	“down-regulates activity”	ACE2	binding
Angiotensin-1	“up-regulates activity”	ACE2	binding
ACE2	“up-regulates quantity”	“Angiotensin 1-7”	cleavage
ACE2	up-regulates	“Receptor_mediated_ endocytosis”
ACE2	up-regulates	Membrane_fusion
ACE2	“up-regulates activity”	AGT	cleavage
ACE2	“up-regulates activity”	APLN	cleavage
ACE2	“up-regulates activity”	Angiotensin-1	cleavage
chloroquine	“down-regulates activity”	ACE2	“chemical inhibition”
ACE2	“form complex”	“Spike protein-ACE2”	binding
ACE2	“form complex”	“CoV2 Spike protein-ACE2”	binding
captopril	“down-regulates activity”	ACE2	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Peptide ligand-binding receptors	6	21.2×	3e-05
GPCR downstream signalling	5	10.3×	2e-03
Signaling by GPCR	5	9.5×	3e-03
Hemostasis	5	8.6×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrin-mediated signaling pathway	5	38.2×	7e-05
angiogenesis	5	14.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

329 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	2
Uncertain significance	64
Likely benign	11
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
144335	GRCh38/hg38 Xp22.33-11.22(chrX:10701-52857805)x1	Pathogenic
145166	GRCh38/hg38 Xp22.33-q11.1(chrX:10701-62712219)x1	Pathogenic
145623	GRCh38/hg38 Xp22.33-11.22(chrX:10679-52857805)x3	Pathogenic
145973	GRCh38/hg38 Xp22.33-21.1(chrX:233335-37292980)x1	Pathogenic
146239	GRCh38/hg38 Xp22.33-21.1(chrX:10679-36186635)x1	Pathogenic
146637	GRCh38/hg38 Xp22.33-22.2(chrX:2936461-17287323)x2	Pathogenic
148018	GRCh38/hg38 Xp22.33-11.22(chrX:10679-52213731)x1	Pathogenic
148177	GRCh38/hg38 Xp22.33-22.2(chrX:10679-16187419)x1	Pathogenic
148356	GRCh38/hg38 Xp22.33-11.22(chrX:10701-52033734)x1	Pathogenic
148957	GRCh38/hg38 Xp22.33-21.1(chrX:10701-37723318)x1	Pathogenic
149009	GRCh38/hg38 Xp22.2-21.2(chrX:12254555-30410580)x1	Pathogenic
152052	GRCh38/hg38 Xp22.33-11.22(chrX:10701-53750424)x1	Pathogenic
153302	GRCh38/hg38 Xp22.33-11.22(chrX:251879-50289363)x1	Pathogenic
153753	GRCh38/hg38 Xp22.33-11.22(chrX:251880-51643625)x1	Pathogenic
153789	GRCh38/hg38 Xp22.33-22.2(chrX:251879-16967290)x1	Pathogenic
154249	GRCh38/hg38 Xp22.33-q12(chrX:251880-66445845)x1	Pathogenic
155429	GRCh38/hg38 Xp22.33-21.1(chrX:251879-35885004)x1	Pathogenic
1703581	GRCh37/hg19 Xp22.33-11.22(chrX:168546-52573789)	Pathogenic
2424508	NC_000023.10:g.(?14861689)(15870650_?)del	Pathogenic
253489	GRCh37/hg19 Xp22.33-21.1(chrX:71267-35809046)x1	Pathogenic
253571	GRCh37/hg19 Xp22.33-11.21(chrX:70297-58066465)x1	Pathogenic
2685690	GRCh37/hg19 Xp22.33-11.22(chrX:2696762-53113314)x1	Pathogenic
2685727	GRCh37/hg19 Xp22.33-21.2(chrX:168547-30774453)x2	Pathogenic
3062471	GRCh37/hg19 Xp22.33-11.21(chrX:168546-55653170)	Pathogenic
3391945	GRCh37/hg19 Xp22.33-21.3(chrX:2631638-25008584)x1	Pathogenic
3391948	GRCh37/hg19 Xp22.2-11.23(chrX:15392463-48777470)x1	Pathogenic
441856	GRCh37/hg19 Xp22.33-11.21(chrX:168546-57683964)x1	Pathogenic
441995	GRCh37/hg19 Xp22.33-21.2(chrX:168546-31085327)x1	Pathogenic
442067	GRCh37/hg19 Xp22.33-11.21(chrX:168546-57504183)x1	Pathogenic
442162	GRCh37/hg19 Xp22.33-11.21(chrX:168546-55240087)x1	Pathogenic

SpliceAI

4868 predictions. Top by Δscore:

Variant	Effect	Δscore
X:15508340:TTTA:T	acceptor_loss	1.0000
X:15508342:TA:T	acceptor_loss	1.0000
X:15508343:A:AG	acceptor_gain	1.0000
X:15508343:AGG:A	acceptor_loss	1.0000
X:15508343:AGGAT:A	acceptor_gain	1.0000
X:15508344:G:GG	acceptor_gain	1.0000
X:15508344:GGAT:G	acceptor_gain	1.0000
X:15508344:GGATG:G	acceptor_gain	1.0000
X:15509328:GAAAA:G	acceptor_gain	1.0000
X:15516211:G:GT	donor_gain	1.0000
X:15516225:G:GT	donor_gain	1.0000
X:15516225:G:T	donor_gain	1.0000
X:15516228:GCAT:G	donor_gain	1.0000
X:15517989:GAGTG:G	donor_gain	1.0000
X:15517991:GTG:G	donor_gain	1.0000
X:15522547:G:T	donor_gain	1.0000
X:15525284:GCA:G	acceptor_loss	1.0000
X:15525285:CA:C	acceptor_loss	1.0000
X:15525286:A:AG	acceptor_gain	1.0000
X:15525287:G:GT	acceptor_gain	1.0000
X:15525287:GT:G	acceptor_gain	1.0000
X:15525287:GTA:G	acceptor_gain	1.0000
X:15525287:GTAGC:G	acceptor_gain	1.0000
X:15526039:AAG:A	acceptor_gain	1.0000
X:15526040:A:G	acceptor_gain	1.0000
X:15526093:TGA:T	donor_gain	1.0000
X:15526093:TGAG:T	donor_loss	1.0000
X:15526094:GA:G	donor_gain	1.0000
X:15526094:GAG:G	donor_gain	1.0000
X:15526095:AGTG:A	donor_loss	1.0000

AlphaMissense

5375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:15575781:C:G	A443P	0.998
X:15587836:A:G	L240P	0.997
X:15575733:A:G	W459R	0.996
X:15575733:A:T	W459R	0.996
X:15575738:T:A	E457V	0.996
X:15585552:A:G	W275R	0.996
X:15585552:A:T	W275R	0.996
X:15575729:C:G	R460T	0.995
X:15571765:A:G	W566R	0.994
X:15571765:A:T	W566R	0.994
X:15575728:C:A	R460S	0.994
X:15575728:C:G	R460S	0.994
X:15571677:A:G	L595P	0.993
X:15572296:G:C	F523L	0.993
X:15572296:G:T	F523L	0.993
X:15572298:A:G	F523L	0.993
X:15575729:C:A	R460M	0.993
X:15575752:A:C	F452L	0.993
X:15575752:A:T	F452L	0.993
X:15575754:A:G	F452L	0.993
X:15575777:A:G	L444P	0.993
X:15571763:C:A	W566C	0.992
X:15571763:C:G	W566C	0.992
X:15575679:A:G	W477R	0.992
X:15575679:A:T	W477R	0.992
X:15575727:A:G	W461R	0.992
X:15575727:A:T	W461R	0.992
X:15585550:C:A	W275C	0.991
X:15585550:C:G	W275C	0.991
X:15575766:C:A	G448W	0.990

dbSNP variants (sampled 300 via entrez): RS1000009210 (X:15527253 T>C,G), RS1000074234 (X:15572914 C>T), RS1000204510 (X:15597673 A>G), RS1000216366 (X:15544003 C>G,T), RS1000257124 (X:15598217 A>C), RS1000332058 (X:15525745 G>A), RS1000352992 (X:15594087 A>T), RS1000366511 (X:15526150 T>A,G), RS1000389895 (X:15565734 T>C), RS1000510959 (X:15551215 T>C), RS1000548845 (X:15541278 G>A,C), RS1000695708 (X:15563283 C>T), RS1000813309 (X:15550788 A>G), RS1000860033 (X:15576067 T>C), RS1000927285 (X:15573260 T>C)

Disease associations

OMIM: gene MIM:300335 | disease phenotypes: MIM:227650, MIM:300868, MIM:308350

GenCC curated gene-disease

Mondo (5): Turner syndrome (MONDO:0019499), Fanconi anemia (MONDO:0019391), multiple congenital anomalies-hypotonia-seizures syndrome 2 (MONDO:0010466), genetic developmental and epileptic encephalopathy (MONDO:0100062), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Turner syndrome (Orphanet:881), Fanconi anemia (Orphanet:84), Multiple congenital anomalies-hypotonia-seizures syndrome type 2 (Orphanet:300496)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D065886	Neurodevelopmental Disorders	F03.625
D014424	Turner Syndrome	C12.050.351.875.253.309.872; C12.050.351.875.253.795.750; C12.200.706.316.309.872; C12.200.706.316.795.750; C12.800.316.309.872; C12.800.316.795.750; C14.240.400.980; C14.280.400.980; C16.131.240.400.970; C16.131.260.830.835.750; C16.131.939.316.309.872; C16.131.939.316.795.750; C16.320.180.830.835.750; C19.391.119.309.872; C19.391.119.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096989 (PROTEIN FAMILY), CHEMBL3736 (SINGLE PROTEIN), CHEMBL4888460 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 508,804 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1560	CAPTOPRIL	4	66,415
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL1201284	CINACALCET	4	5,917
CHEMBL1535	HYDROXYCHLOROQUINE	4	42,638
CHEMBL76	CHLOROQUINE	4	58,679
CHEMBL35241	DIMINAZENE	2	1,993
CHEMBL449782	CEPHARANTHINE	2	3,066
CHEMBL429844	ORE-1001	1	156

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2106809	Efficacy	3	captopril	Hypertension

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2106809	ACE2	3	0.50	1	captopril
rs2285666	ACE2		0.00	0
rs2074192	ACE2		0.00	0
rs4240157	ACE2		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M2: Angiotensin-converting enzymes (ACE and ACE2)

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
compound 28 [PMID: 18324760]	Inhibition	9.9	pKi
MLN-4760	Inhibition	9.36	pIC50
BCY15291	Inhibition	9.05	pKi
DX600	Inhibition	8.55	pKi
CPS4	Binding	6.2	pIC50
XNT [PMID: 18391097]	Activation	4.7	pEC50

Binding affinities (BindingDB)

30 measured of 36 human assays (36 total across all organisms); most potent 30 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
The second fraction of the HPLC chromatogram.	KI	0.13 nM
3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid	KI	0.4 nM
MLN4760	IC50	0.44 nM
The second fraction of the HPLC chromatogram.	KI	0.7 nM
3-{1-(2-acetamido-4-methylpentanoyl)pyrrolidin-2-ylphosphoryl}-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid	KI	1.25 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(3,5-dimethylphenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	1.4 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(3-methylphenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	4.2 nM
2-benzyl-3-({1-[2-acetamido-3-(4-hydroxyphenyl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)propanoic acid	KI	5.2 nM
2-benzyl-3-{1-(2-acetamido-3-phenylpropanoyl)pyrrolidin-2-ylphosphoryl}propanoic acid	KI	5.2 nM
3-{1-(6-amino-2-acetamidohexanoyl)pyrrolidin-2-ylphosphoryl}-2-benzylpropanoic acid	KI	6.5 nM
2-benzyl-3-{1-(2-acetamido-3-methylbutanoyl)pyrrolidin-2-ylphosphoryl}propanoic acid	KI	6.6 nM
5-{2-[(2-benzyl-2-carboxyethyl)(hydroxy)phosphoryl]pyrrolidin-1-yl}-4-acetamido-5-oxopentanoic acid	KI	7 nM
2-benzyl-3-{1-(2-acetamidopropanoyl)pyrrolidin-2-ylphosphoryl}propanoic acid	KI	7.5 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(3,4-dimethylphenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	10 nM
(2S)-2-{[(1S)-1-carboxy-2-[1-(2-cyclohexylpropan-2-yl)-1H-imidazol-5-yl]ethyl]amino}-4-methylpentanoic acid	IC50	10 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(4-chlorophenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	21 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(4-methylphenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	32 nM
(2S)-2-{[(1S)-1-carboxy-2-(1-{[4-(trifluoromethoxy)phenyl]methyl}-1H-imidazol-5-yl)ethyl]amino}-4-methylpentanoic acid	IC50	52 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(4-nitrophenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	76 nM
3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanamido]-3-methylbutyl}(hydroxy)phosphoryl)-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid	KI	220 nM
(2S)-2-{[(1S)-1-carboxy-2-[1-(cyclohexylmethyl)-1H-imidazol-5-yl]ethyl]amino}-4-methylpentanoic acid	IC50	270 nM
(2S)-2-{[(1S)-1-carboxy-2-{1-[(2-methylphenyl)methyl]-1H-imidazol-5-yl}ethyl]amino}-4-methylpentanoic acid	IC50	290 nM
2-benzyl-3-({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)propanoic acid	KI	300 nM
2-[({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)methyl]-4-methylpentanoic acid	KI	300 nM
(2S)-2-{[(1S)-2-(1-benzyl-1H-imidazol-5-yl)-1-carboxyethyl]amino}butanoic acid	IC50	300 nM
(2S)-2-{[(1S)-2-(1-benzyl-1H-imidazol-5-yl)-1-carboxyethyl]amino}-3-phenylpropanoic acid	IC50	340 nM
2-benzyl-3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanamido]-3-methylbutyl}(hydroxy)phosphoryl)propanoic acid	KI	800 nM
2-benzyl-3-{1-(2-acetamido-4-methylpentanamido)-2-phenylethylphosphoryl}propanoic acid	KI	920 nM
3-({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)-2-methylpropanoic acid	KI	3000 nM
2-benzyl-3-[(1-{[(benzyloxy)carbonyl]amino}-3-methylbutyl)(hydroxy)phosphoryl]propanoic acid	KI	8000 nM

ChEMBL bioactivities

238 potent at pChembl≥5 of 269 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.31	Kd	0.049	nM	CHEMBL5430631
10.27	Kd	0.054	nM	CHEMBL5424883
10.24	Kd	0.057	nM	CHEMBL5406655
10.22	Kd	0.06	nM	CHEMBL5394399
9.89	Ki	0.13	nM	CHEMBL260273
9.66	Ki	0.22	nM	CHEMBL5430631
9.54	Ki	0.29	nM	CHEMBL5394399
9.52	Ki	0.3	nM	CHEMBL5406655
9.46	Ki	0.35	nM	CHEMBL260273
9.46	Ki	0.35	nM	CHEMBL5424883
9.40	Ki	0.4	nM	CHEMBL409105
9.36	IC50	0.44	nM	ORE-1001
9.36	IC50	0.44	nM	CHEMBL5279656
9.36	Kd	0.44	nM	CHEMBL5395954
9.31	IC50	0.49	nM	CHEMBL5430631
9.19	IC50	0.64	nM	CHEMBL5394399
9.19	IC50	0.65	nM	CHEMBL5406655
9.15	Ki	0.7	nM	CHEMBL261423
9.14	Kd	0.72	nM	CHEMBL5429094
9.11	IC50	0.78	nM	CHEMBL5424883
9.07	Ki	0.85	nM	CHEMBL251808
9.05	Ki	0.9	nM	CHEMBL251804
9.05	Ki	0.89	nM	CHEMBL5395954
9.00	IC50	1	nM	CHEMBL5281591
9.00	IC50	1	nM	CHEMBL95564
8.92	Ki	1.2	nM	CHEMBL5403774
8.92	Ki	1.2	nM	CHEMBL5429094
8.92	Kd	1.2	nM	CHEMBL5403774
8.90	Ki	1.25	nM	CHEMBL261121
8.90	IC50	1.259	nM	CHEMBL5220314
8.89	Ki	1.3	nM	CHEMBL253224
8.89	Kd	1.3	nM	CHEMBL5415414
8.85	Ki	1.4	nM	CHEMBL271225
8.85	Ki	1.4	nM	CHEMBL257726
8.82	Ki	1.5	nM	CHEMBL252391
8.82	Ki	1.5	nM	CHEMBL400526
8.82	Ki	1.5	nM	CHEMBL269997
8.82	Ki	1.5	nM	CHEMBL5424641
8.82	Ki	1.5	nM	CHEMBL5415414
8.82	IC50	1.5	nM	CHEMBL5395954
8.80	Ki	1.6	nM	CHEMBL269996
8.80	Kd	1.6	nM	CHEMBL5396932
8.77	Kd	1.7	nM	CHEMBL5433480
8.74	Ki	1.8	nM	CHEMBL404117
8.74	Ki	1.8	nM	CHEMBL257270
8.73	IC50	1.88	nM	CHEMBL5273921
8.72	Kd	1.9	nM	CHEMBL5424641
8.70	Ki	2	nM	CHEMBL398771
8.70	IC50	2	nM	CHEMBL5395954
8.70	Ki	2	nM	CHEMBL5429562

PubChem BioAssay actives

246 with measured affinity, of 464 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-33,36,46-tris(hydroxymethyl)-12-(1H-imidazol-4-ylmethyl)-43-[(4-methylphenyl)methyl]-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	<0.0001	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-43-benzyl-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-33,36,46-tris(hydroxymethyl)-12-(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0001	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-43-[(4-fluorophenyl)methyl]-33,36,46-tris(hydroxymethyl)-12-(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0001	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-43-[(4-chlorophenyl)methyl]-33,36,46-tris(hydroxymethyl)-12-(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0001	uM
(2S)-2-[[[(2S)-1-[(2S)-2-acetamido-4-methylpentanoyl]pyrrolidin-2-yl]-hydroxyphosphoryl]methyl]-3-phenylpropanoic acid	331168: Inhibition of ACE2	ki	0.0001	uM
[1-(2-acetamido-4-methylpentanoyl)-2,3-dihydropyrrol-5-yl]-(2-carboxy-3-phenylpropyl)-dihydroxyphosphanium	1798086: Enzyme Inhibition Assay from Article 10.1021/jm701275z: “Development of Potent and Selective Phosphinic Peptide Inhibitors of Angiotensin-Converting Enzyme 2.”	ki	0.0001	uM
(2S)-2-[[(9R,12S,15S,18S,21S,27S,30S,33S,36S,39R,42S,45S,48S,51S,54R)-54-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,48-bis(3-carbamimidamidopropyl)-33,36,45-tris(hydroxymethyl)-12,42-bis(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,38,41,44,47,50,53,59,62-heptadecaoxo-51-propan-2-yl-7,56,65-trithia-1,3,10,13,16,19,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[37.22.5.13,60.021,25]heptahexacontane-9-carbonyl]amino]propanoic acid	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0004	uM
2-[[[(2S)-1-[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]-hydroxyphosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoic acid	331168: Inhibition of ACE2	ki	0.0004	uM
(2S)-2-[[(1S)-1-carboxy-2-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]ethyl]amino]-4-methylpentanoic acid	1560682: Inhibition of ACE2 (unknown origin)	ic50	0.0004	uM
[1-[2-acetamido-3-(1H-imidazol-5-yl)propanoyl]-2,3-dihydropyrrol-5-yl]-[2-carboxy-3-(3-phenyl-1,2-oxazol-5-yl)propyl]-dihydroxyphosphanium	1798086: Enzyme Inhibition Assay from Article 10.1021/jm701275z: “Development of Potent and Selective Phosphinic Peptide Inhibitors of Angiotensin-Converting Enzyme 2.”	ki	0.0004	uM
2-[[1-carboxy-2-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]ethyl]amino]-4-methylpentanoic acid	1804127: No assay is provided from Article 10.1002/med.21724: “The recent outbreaks of human coronaviruses: A medicinal chemistry perspective.”	ic50	0.0004	uM
(2S)-2-[[(9R,12S,15S,18S,21S,27S,30S,33S,36S,39R,42S,45S,48S,51S,54R)-54-[[(2S)-2-acetamidopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,48-bis(3-carbamimidamidopropyl)-33,36,45-tris(hydroxymethyl)-12,42-bis(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,38,41,44,47,50,53,59,62-heptadecaoxo-51-propan-2-yl-7,56,65-trithia-1,3,10,13,16,19,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[37.22.5.13,60.021,25]heptahexacontane-9-carbonyl]amino]propanoic acid	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0007	uM
(2S)-2-[[[(2S)-1-[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]pyrrolidin-2-yl]-hydroxyphosphoryl]methyl]-3-phenylpropanoic acid	331168: Inhibition of ACE2	ki	0.0007	uM
[1-[2-acetamido-3-(1H-imidazol-5-yl)propanoyl]-2,3-dihydropyrrol-5-yl]-(2-carboxy-3-phenylpropyl)-dihydroxyphosphanium	1798086: Enzyme Inhibition Assay from Article 10.1021/jm701275z: “Development of Potent and Selective Phosphinic Peptide Inhibitors of Angiotensin-Converting Enzyme 2.”	ki	0.0007	uM
(2S)-3-[4-[(3,4-difluorophenyl)methoxy]phenyl]-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0008	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(2-phenoxyphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0009	uM
benzyl N-[5-[[3-[formyl(hydroxy)amino]-2-(2-methylpropyl)hexanoyl]amino]-6-oxo-6-(1,3-thiazol-2-ylamino)hexyl]carbamate	1804127: No assay is provided from Article 10.1002/med.21724: “The recent outbreaks of human coronaviruses: A medicinal chemistry perspective.”	ic50	0.0010	uM
(2S)-1-[(2R,5S)-5-benzamido-2-methyl-4-oxo-6-phenylhexanoyl]pyrrolidine-2-carboxylic acid	39752: Inhibition of guinea pig serum Angiotensin I converting enzyme	ic50	0.0010	uM
benzyl N-[(5S)-5-[[(2R,3S)-3-[formyl(hydroxy)amino]-2-(2-methylpropyl)hexanoyl]amino]-6-oxo-6-(1,3-thiazol-2-ylamino)hexyl]carbamate	1927252: Inhibition of human recombinant ACE2 at 50 uM using (7Mca-Y-V-A- D -A-P- K(Knp) as a flurogenic substrate measured after 10 mins by fluorescence based analysis	ic50	0.0010	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,39R,42S,45S,48S,54R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-45-(3-amino-3-oxopropyl)-54-[[(2S)-2-aminopropanoyl]amino]-42-benzyl-18,48-bis(3-carbamimidamidopropyl)-33-[(1R)-1-hydroxyethyl]-15,36-bis(1H-imidazol-4-ylmethyl)-12,30-bis(2-methylpropyl)-27-(2-methylsulfanylethyl)-4,11,14,17,20,26,29,32,35,38,41,44,47,50,53,59,62-heptadecaoxo-7,56,65-trithia-1,3,10,13,16,19,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[37.22.5.13,60.021,25]heptahexacontane-9-carboxamide	1997770: Binding affinity to human ACE2 assessed as inhibition constant by surface plasmon resonance analysis	ki	0.0012	uM
(9R,12S,15S,18S,21S,23S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-23-hydroxy-33,36,46-tris(hydroxymethyl)-12,43-bis(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0013	uM
(2S)-3-(4-hydroxyphenyl)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0013	uM
2-[[[(2S)-1-[(2S)-2-acetamido-4-methylpentanoyl]pyrrolidin-2-yl]-hydroxyphosphoryl]methyl]-3-(3-phenyl-1,2-oxazol-5-yl)propanoic acid	331168: Inhibition of ACE2	ki	0.0013	uM
(2R)-2-[[(1S)-1-carboxy-2-[3-[(3,5-dichlorophenyl)methyl]imidazol-4-yl]ethyl]amino]-4-methylpentanoic acid	1916554: Inhibition of recombinant human ACE2 using 7-Mca-YVADAPK (Dnp) as substrate by fluorescence plate reader assay	ic50	0.0013	uM
[1-(2-acetamido-4-methylpentanoyl)-2,3-dihydropyrrol-5-yl]-[2-carboxy-3-(3-phenyl-1,2-oxazol-5-yl)propyl]-dihydroxyphosphanium	1798086: Enzyme Inhibition Assay from Article 10.1021/jm701275z: “Development of Potent and Selective Phosphinic Peptide Inhibitors of Angiotensin-Converting Enzyme 2.”	ki	0.0013	uM
(2S)-2-[[(1S)-1-carboxy-2-[3-[(3,5-dimethylphenyl)methyl]imidazol-4-yl]ethyl]amino]-4-methylpentanoic acid	1798089: Enzyme Inhibition Assay from Article 10.1021/ja0277226: “Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors.”	ic50	0.0014	uM
(2S)-3-(4-phenylphenyl)-2-[[(2S)-2-sulfanylbutanoyl]amino]propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0014	uM
(2S)-2-[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenylphenyl)propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0014	uM
2-[(9R,12S,15S,18S,21S,27S,30S,33R,36S,40R,43S,46S,49S,52S,55R)-9-[[(2S)-1-amino-1-oxopropan-2-yl]carbamoyl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-36,46-bis(hydroxymethyl)-12,43-bis(1H-imidazol-4-ylmethyl)-21-methyl-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontan-33-yl]acetic acid	1997770: Binding affinity to human ACE2 assessed as inhibition constant by surface plasmon resonance analysis	ki	0.0015	uM
(2S)-2-[[(2S)-3-methyl-2-sulfanylbutanoyl]amino]-3-(4-phenylphenyl)propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0015	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenylphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0015	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-phenylpropanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0015	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,39R,42S,45S,51S,54S,57R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-57-[[(2S)-2-aminopropanoyl]amino]-18,51-bis(3-carbamimidamidopropyl)-12,54-bis[(1R)-1-hydroxyethyl]-33-(hydroxymethyl)-36-(1H-imidazol-4-ylmethyl)-42-(1H-indol-3-ylmethyl)-15-methyl-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,38,41,44,50,53,56,62,65-heptadecaoxo-7,59,68-trithia-1,3,10,13,16,19,25,28,31,34,37,40,43,49,52,55,63-heptadecazapentacyclo[37.25.5.13,63.021,25.045,49]heptacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0016	uM
(2S)-2-[[(2S,3S)-3-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenylphenyl)propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0016	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-55-amino-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-33,36,46-tris(hydroxymethyl)-12,43-bis(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0017	uM
(2S)-2-[[(2S)-2-cyclopentyl-2-sulfanylacetyl]amino]-3-(4-phenylphenyl)propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0018	uM
(2S)-3-(4-phenylphenyl)-2-[[(2S)-2-sulfanylhexanoyl]amino]propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0018	uM
(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylsulfanylbutanoic acid	1927259: Inhibition of SARS-CoV S binding to human recombinant ACE2 expressed in Escherichia coli BL21(DE3) incubated for 2 hrs by ELISA method	ic50	0.0019	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-55-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-30-(2,2-dimethylpropyl)-33,36,46-tris(hydroxymethyl)-12,43-bis(1H-imidazol-4-ylmethyl)-27-(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997770: Binding affinity to human ACE2 assessed as inhibition constant by surface plasmon resonance analysis	ki	0.0020	uM
(2S)-3-[4-[(2,4-difluorophenyl)methoxy]phenyl]-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0020	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-naphthalen-1-ylpropanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0022	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(3-phenylphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0022	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenoxyphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0022	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-naphthalen-2-ylpropanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0024	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(3-phenylmethoxyphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0024	uM
(2S)-2-[[(2S)-2-cyclobutyl-2-sulfanylacetyl]amino]-3-(4-phenylphenyl)propanoic acid	317218: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0024	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,39R,42S,45R,48S,51S,54R)-N-[(2S)-1-amino-1-oxopropan-2-yl]-54-[[(2S)-2-aminopropanoyl]amino]-15-[(2S)-butan-2-yl]-51-tert-butyl-18,48-bis(3-carbamimidamidopropyl)-33,36,45-tris(hydroxymethyl)-12,42-bis(1H-imidazol-4-ylmethyl)-29-methylidene-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,32,35,38,41,44,47,50,53,59,62-hexadecaoxo-7,56,65-trithia-1,3,10,13,16,19,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[37.22.5.13,60.021,25]heptahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0025	uM
(2S)-3-[4-[(4-fluorophenyl)methoxy]phenyl]-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0025	uM
(9R,12S,15S,18S,21S,27S,30S,33S,36S,40R,43S,46S,49S,52S,55R)-55-acetamido-15-[(2S)-butan-2-yl]-18,49-bis(3-carbamimidamidopropyl)-33,36,46-tris(hydroxymethyl)-12,43-bis(1H-imidazol-4-ylmethyl)-27,30-bis(2-methylpropyl)-4,11,14,17,20,26,29,32,35,39,42,45,48,51,54,60,63-heptadecaoxo-52-propan-2-yl-7,57,66-trithia-1,3,10,13,16,19,25,28,31,34,37,38,41,44,47,50,53,61-octadecazatetracyclo[38.22.5.13,61.021,25]octahexacontane-9-carboxamide	1997771: Binding affinity to human ACE2 assessed as binding constant by surface plasmon resonance analysis	kd	0.0027	uM
(2S)-2-[[(2S,3R)-3-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenylmethoxyphenyl)propanoic acid	314424: Inhibition of human recombinant ACE2 by fluorescence assay	ki	0.0027	uM

CTD chemical–gene interactions

112 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benazepril	increases response to substance, affects cotreatment, affects response to substance	3
Doxorubicin	decreases expression, increases expression	3
DX600 peptide	decreases activity	2
Etoposide	decreases expression, increases expression	2
Hydroxyzine	increases activity, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	affects expression	2
resorcinolnaphthalein	affects activity	1
tannic acid	decreases expression	1
diminazene aceturate	affects cotreatment, affects reaction, decreases reaction, increases expression, increases phosphorylation (+1 more)	1
pirinixic acid	affects binding, decreases expression, increases activity	1
potassium perchlorate	decreases reaction, increases expression	1
Lugol’s solution	decreases reaction, increases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
nimesulide	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	increases expression	1
hydroquinone	decreases expression	1
pentanal	increases expression	1
imidapril	increases response to substance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects reaction, decreases expression	1
nicotianamine	decreases activity	1
CGP 52608	affects binding, increases reaction	1
2,7-dihydroxynaphthalene	decreases expression	1
angiotensin I (1-7)	increases abundance, increases cleavage	1
desloratadine	affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid	decreases activity	1
angiotensin I (1-9)	increases abundance, increases cleavage	1

ChEMBL screening assays

107 unique, capped per target: 98 binding, 6 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL644716	Binding	Inhibition of Angiotensin I converting enzyme	Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by tricyclic benzazepinone thiols — Bioorg Med Chem Lett
CHEMBL647713	Functional	Time to inhibit maximum Angiotensin I converting enzyme in Hog plasma	Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives. — J Med Chem
CHEMBL4374949	ADMET	Inhibition of human C-terminal His/FLAG-tagged ACE-2 expressed in HEK293 cells at 50 uM preincubated for 10 mins followed by Mca-Ala-Pro-Lys(Dnp)-OH substrate addition by fluorescence assay relative to control	Structure-Based Development of (1-(3’-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-β-lactamases. — J Med Chem

Cellosaurus cell lines

39 cell lines: 18 cancer cell line, 13 transformed cell line, 6 spontaneously immortalized cell line, 1 induced pluripotent stem cell, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5KA	A549-hACE2 [Invivogen]	Cancer cell line	Male
CVCL_A5KB	A549-hACE2-TMPRSS2	Cancer cell line	Male
CVCL_A5TE	sciCHO:hACE2	Spontaneously immortalized cell line	Female
CVCL_A5TF	sciCHO:hACE2:hTMPRSS2	Spontaneously immortalized cell line	Female
CVCL_A7UK	HEK-293T-hACE2	Transformed cell line	Female
CVCL_A7UV	A549-hACE2 [BEI resources]	Cancer cell line	Male
CVCL_A7UW	A549-hACE2 (HA-FLAG)	Cancer cell line	Male
CVCL_A7YK	HEK-Blue hACE2	Transformed cell line	Female
CVCL_A7ZQ	A549-Dual hACE2-TMPRSS2	Cancer cell line	Male
CVCL_A7ZR	A549-Dual KO-MDA5 hACE2-TMPRSS2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00134745	PHASE4	COMPLETED	Defining the Optimal Hormonal Replacement Therapy in Turner Syndrome
NCT00256126	PHASE4	COMPLETED	Predictive Markers in Growth Hormone Deficiency (GHD) and Turner Syndrome (TS) Children Treated With SAIZEN®
NCT00266656	PHASE4	COMPLETED	Long-Term Growth and Skeletal Effects of Early Growth Hormone Treatment in Turner Syndrome
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01245374	PHASE4	COMPLETED	Norditropin NordiFlex® Device Compared to the Device Previously Used by Patients or Parents
NCT01419249	PHASE4	COMPLETED	First Year Growth Response Associated Genetic Markers Validation Phase IV Open-label Study in Growth Hormone Deficient and Turner Syndrome Pre-pubertal Children: the PREDICT Pharmacogenetics Validation Study
NCT01518062	PHASE4	COMPLETED	Safety of Somatropin and Induction of Puberty With 17-beta-oestradiol in Girls With Turner Syndrome
NCT01734486	PHASE4	COMPLETED	Growth Response in Girls With Turner Syndrome
NCT03015909	PHASE4	COMPLETED	Evaluation of the Ease of Use, Preference, and Safety of EutropinPen Inj.
NCT06544473	PHASE4	RECRUITING	Determining Dose Equivalence Between Oral and Transdermal Estrogen Treatment in Women With Turner Syndrome
NCT06570460	PHASE4	RECRUITING	Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome
NCT06834594	PHASE4	RECRUITING	Bleeding Patterns in Sequential and Continuous Progesterone Supplementation in Adolescents With Turner Syndrome
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00029159	PHASE3	COMPLETED	The Effect of Androgen and Growth Hormone on Height and Learning in Girls With Turner Syndrome
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00191113	PHASE3	COMPLETED	Somatropin Treatment to Final Height in Turner Syndrome
NCT00234533	PHASE3	COMPLETED	Study to Define Optimal IGF-1 Monitoring in Children Treated With NutropinAq
NCT00406926	PHASE3	COMPLETED	The Effect of Growth Hormone in Very Young Girls With Turner Syndrome
NCT01518036	PHASE3	COMPLETED	Use of Somatropin in Turner Syndrome
NCT01563926	PHASE3	COMPLETED	Evaluating Acceptance of New Liquid Somatropin Formulation in Children With Growth Hormone Deficiency
NCT01710696	PHASE3	COMPLETED	Induction of Puberty With 17-beta Estradiol in Girls With Turner Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT07221851	PHASE3	RECRUITING	Trial Investigating the Efficacy and Safety of Weekly Lonapegsomatropin Compared to Daily Somatropin in Children and Adolescents With Short Stature or Growth Failure Due to Growth Hormone Sufficient Disorders
NCT07614152	PHASE3	NOT_YET_RECRUITING	The Efficacy and Safety of Inpegsomatropin Injection in Children With Turner Syndrome(TS) and Short Stature
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00001221	PHASE2	COMPLETED	Effect of Biosynthetic Growth Hormone and/or Ethinyl Estradiol on Adult Height in Patients With Turner Syndrome
NCT00001253	PHASE2	COMPLETED	The Effects of Estrogen on Cognition in Girls With Turner Syndrome
NCT03189160	PHASE2	UNKNOWN	A Study of PEG-somatropin Injection to Treat Children of Turner Syndrome
NCT05690386	PHASE2	ACTIVE_NOT_RECRUITING	A Trial to Investigate Different Doses of Lonapegsomatropin Compared to Somatropin in Individuals With Turner Syndrome
NCT05838885	PHASE2	COMPLETED	A Trial of YPEG-rhGH in Children With Short Stature
NCT05849389	PHASE2	RECRUITING	Vosoritide for Short Stature in Turner Syndrome
NCT07041814	PHASE2	NOT_YET_RECRUITING	A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)