TY - JOUR
T1 - Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro)
T2 - In Vitro and In Vivo Antiviral Activity
AU - Velma, Ganga Reddy
AU - Shen, Zhengnan
AU - Holberg, Cameron
AU - Fu, Jiqiang
AU - Soleymani, Farinaz
AU - Cooper, Laura
AU - Ramos, Omar Lozano
AU - Indukuri, Divakar
AU - Musku, Soumya Reddy
AU - Rychetsky, Pavel
AU - Slilaty, Steve
AU - Li, Zuomei
AU - Ratia, Kiira
AU - Rong, Lijun
AU - Schenten, Dominik
AU - Xiong, Rui
AU - J Thatcher, Gregory R.
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/8/22
Y1 - 2024/8/22
N2 - The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro’s featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 infection.
AB - The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro’s featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 infection.
UR - https://www.scopus.com/pages/publications/85200981927
UR - https://www.scopus.com/pages/publications/85200981927#tab=citedBy
U2 - 10.1021/acs.jmedchem.4c00378
DO - 10.1021/acs.jmedchem.4c00378
M3 - Article
C2 - 39102360
AN - SCOPUS:85200981927
SN - 0022-2623
VL - 67
SP - 13681
EP - 13702
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -