Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design
Wrocław University of Science and Technology · AGH University of Krakow · +6 more institutions
Abstract
Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro…
Citation impact
- FWCI
- 9.45
- Percentile
- 100%
- References
- 54
Authors
11- WRWioletta RutCorresponding
Wrocław University of Science and Technology, AGH University of Krakow
- ZLZongyang LvCorresponding
The University of Texas at San Antonio Health Science Center, MUSC Hollings Cancer Center
- MŻMikołaj Żmudziński
Wrocław University of Science and Technology, AGH University of Krakow
- SPStephanie Patchett
New York University
- DNDigant Nayak
The University of Texas at San Antonio Health Science Center, MUSC Hollings Cancer Center
Topics & keywords
- Protease
- Papain
- Chemistry
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- Biology
- Proteases
- Biochemistry
- Computational biology
Funding
- UDU.S. Department of EnergyAwards: AC02-06CH11357, P30 GM124165, DE-AC02, 06CH11357, DE-AC02-06CH11357, DE-AC02-
- MUMedical University of South Carolina
- UOUniversity of South Carolina
- ECEuropean CommissionAward: DE-AC02-06CH11357
- FNFundacja na rzecz Nauki PolskiejAward: TEAM/2017-4/32
- NCNarodowe Centrum NaukiAward: 2015/17/N/ST5/03072
- NINational Institutes of HealthAwards: P30 GM124165, ES025166, R01 GM115568, S10 RR027139-01, DE-AC02-06CH11357, GM124165, GM099040, S10 RR027139
- OOOffice of ScienceAwards: DE-AC02-06CH11357, DE-AC02, 06CH11357, AC02-06CH11357
- EREuropean Regional Development FundAward: TEAM/2017-4/32
- NINational Institute of General Medical SciencesAwards: DE-AC02-06CH11357, P30 GM124165, GM124165
- ANArgonne National LaboratoryAwards: DE-AC02, 06CH11357, P30 GM124165, AC02-06CH11357