Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
Rutgers, The State University of New Jersey · Oklahoma State University
Abstract
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL pro ) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL pro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL pro with the inhibitory constant K i values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL pro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC 50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682…
Citation impact
- FWCI
- 38.45
- Percentile
- 100%
- References
- 50
Authors
13- BTBin TanCorresponding
Rutgers, The State University of New Jersey
- XZXiaoming ZhangCorresponding
Oklahoma State University
- AAAhmadullah AnsariCorresponding
Rutgers, The State University of New Jersey
- PDPrakash D. JadhavCorresponding
Rutgers, The State University of New Jersey
- HTHaozhou Tan
Rutgers, The State University of New Jersey
Topics & keywords
- Protease
- In vivo
- Papain
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- Proteases
- Virology
- Antiviral drug
- Protease inhibitor (pharmacology)
- Good health and well-being