VBY-825   Click here for help

GtoPdb Ligand ID: 10746

Synonyms: VBY825
Compound class: Synthetic organic
Comment: VBY-825 is a reversible cysteine protease inhibitor with high potency against cathepsins B, L, S and V [1]. Human cysteinyl cathepsins are required for proteolytic processing of virally encoded proteins during infection [2-3,5], including a likely requirement for proper processing of the SARS-CoV-2 S protein within the endosome (activating its fusogenic acitivity) [5]. Experimental evidence indicates that VBY-825 has some antiviral activity against SARS-CoV-2 [4]. In in vitro experiments VBY-825 inhibits SARS-CoV-2 entry. It does not inhibit the viral 3C-like protease (3CLpro) or papain-like protease (PLpro), which suggests that its antiviral activity is associated with inhibition of host proteases.

In the oncology setting, a pre-clinical model of pancreatic islet cancer revealed that VBY-825 exhibits significant anti-tumour activity.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 16
Topological polar surface area 129.82
Molecular weight 535.18
XLogP 3.24
No. Lipinski's rules broken 1
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Canonical SMILES CC[C@@H](C(=O)C(=O)NC1CC1)NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@H](C(F)(F)F)c1ccc(cc1)F
Isomeric SMILES CC[C@@H](C(=O)C(=O)NC1CC1)NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@H](C(F)(F)F)c1ccc(cc1)F
InChI InChI=1S/C23H29F4N3O5S/c1-2-17(19(31)22(33)28-16-9-10-16)30-21(32)18(12-36(34,35)11-13-3-4-13)29-20(23(25,26)27)14-5-7-15(24)8-6-14/h5-8,13,16-18,20,29H,2-4,9-12H2,1H3,(H,28,33)(H,30,32)/t17-,18-,20-/m0/s1
1. Elie BT, Gocheva V, Shree T, Dalrymple SA, Holsinger LJ, Joyce JA. (2010)
Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model.
Biochimie, 92 (11): 1618-24. [PMID:20447439]
2. Marzi A, Reinheckel T, Feldmann H. (2012)
Cathepsin B & L are not required for ebola virus replication.
PLoS Negl Trop Dis, 6 (12): e1923. [PMID:23236527]
3. Mori Y, Yamashita T, Tanaka Y, Tsuda Y, Abe T, Moriishi K, Matsuura Y. (2007)
Processing of capsid protein by cathepsin L plays a crucial role in replication of Japanese encephalitis virus in neural and macrophage cells.
J Virol, 81 (16): 8477-87. [PMID:17553875]
4. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, Burgstaller-Muehlbacher S, De Jesus PD, Teriete P, Hull MV et al.. (2020)
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Nature, [Epub ahead of print]. DOI: 10.1038/s41586-020-2577-1
5. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. (2005)
Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry.
Proc Natl Acad Sci USA, 102 (33): 11876-81. [PMID:16081529]