Audrey Labbe
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Research Subjects
Audrey Labbe has a total of 32 co-authors. Here are the top co-authors by number of shared publications:
- Andrzej Joachimiak
BERlight and Structural Biology Center, X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Lemont, Illinois, USA
1 shared publication - Babak Andi
Center for BioMolecular Structure, National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, USA
1 shared publication - Brett L. Hurst
Institute for Antiviral Research, Utah State University, 5600 Old Main Hill VSB 202, Logan, UT, 84322, United States; Department of Veterinary, Clinical and Life Sciences, Utah State University, 4700 Old Main Hill CIB 213, Logan, UT, 84322, United States
1 shared publication - Brian C. Sanders
Oak Ridge National Laboratory
1 shared publication Christopher Rainville
Progenra Inc
1 shared publication- Colleen B. Jonsson
Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
1 shared publication
Latest Publications
- Open Access
- 21 July 2022
- Published by Springer Nature in Research Square
Potent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2
Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with kinact/KI = 10,000 M− 1 s− 1, achieved sub-µM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at > 30 µM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validated our design strategy and established the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.
- 21 July 2022
- Published by Springer Nature in Research Square
Open AccessPotent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2
Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with kinact/KI = 10,000 M− 1 s− 1, achieved sub-µM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at > 30 µM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validated our design strategy and established the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.