2. Academic Validation
  3. Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay

Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay

  • ACS Cent Sci. 2021 Jul 28;7(7):1245-1260. doi: 10.1021/acscentsci.1c00519.
Chunlong Ma 1,  Michael Dominic Sacco 2,  Zilei Xia 1,  George Lambrinidis 3,  Julia Alma Townsend 4,  Yanmei Hu 1,  Xiangzhi Meng 5,  Tommy Szeto 1,  Mandy Ba 1,  Xiujun Zhang 2,  Maura Gongora 2,  Fushun Zhang 5,  Michael Thomas Marty 4,  Yan Xiang 5,  Antonios Kolocouris 3,  Yu Chen 2,  Jun Wang 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • 2 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • 3 Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, 15771 Athens, Greece.
  • 4 Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
  • 5 Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
PMID: 34341772 DOI: 10.1021/acscentsci.1c00519
Abstract

The papain-like Protease (PLpro) of SARS-CoV-2 is a validated Antiviral drug target. Through a fluorescence resonance energy transfer-based high-throughput screening and subsequent lead optimization, we identified several PLpro inhibitors including Jun9-72-2 and Jun9-75-4 with improved enzymatic inhibition and Antiviral activity compared to GRL0617, which was reported as a SARS-CoV PLpro inhibitor. Significantly, we developed a cell-based FlipGFP assay that can be applied to predict the cellular Antiviral activity of PLpro inhibitors in the BSL-2 setting. X-ray crystal structure of PLpro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to a more closed conformation. Molecular dynamics simulations showed that Jun9-72-2 and Jun9-75-4 engaged in more extensive interactions than GRL0617. Overall, the PLpro inhibitors identified in this study represent promising candidates for further development as SARS-CoV-2 antivirals, and the FlipGFP-PLpro assay is a suitable surrogate for screening PLpro inhibitors in the BSL-2 setting.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z