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UbiQ-news: Anti–COVID-19 Drug Design


Farid El Oualid


18 November 2020
Anti–COVID-19 Drug Design by targeting a molecular scissor of Ubiquitin and ISG15

The global epidemic of three coronaviruses has emerged in this century so far: SARS-CoV-1 in 2002, MERS-CoV in 2012 and SARS-CoV-2 in 2019. Current studies indicate that SARS-CoV-2 is similar to SARS-CoV-1. Although these three coronaviruses are identified as highly pathogenic for humans, there is no effective antiviral treatment. Therefore, current studies are focused on rapid development of vaccines and antiviral drugs to prevent and treat coronavirus infection.

PLpro (NSP3) is a viral papain-like cysteine protease that is essential for SARS-CoV-2 replication. Because of this it represents a promising target for the development of antiviral drugs.
UbiQ is proud to have been part of a major collaboration reported recently by Rut et al. in Science Advances, describing the activity profiling and crystal structures of inhibitor bound SARS-CoV-2 PLpro. Using a combinatorial substrate library and comprehensive activity profiling of SARS-CoV-2 PLpro afforded two promising PLpro inhibitors, called VIR250 and VIR251. On the scaffold of the best hits from positional scanning, optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro were designed. Crystal structures of VIR250 (Figure 1) and VIR251 in complex with SARS-CoV-2 PLpro revealed their inhibitory mechanisms and provide a molecular basis for the observed substrate specificity profiles. SARS-CoV-2 PLpro was also demonstrated to harbor deISGylating activity similar to SARS-CoV-1 PLpro but its ability to hydrolyze K48-linked ubiquitin chains is diminished. Overall, the reported work reveals the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.
Figure 1. Crystal structure of SARS CoV-2 PLPro in complex with inhibitor VIR250 (pdb 6WUU).

Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design. 
Wioletta Rut (1,*,†), Zongyang Lv (2,3,*), Mikolaj Zmudzinski (1), Stephanie Patchett (4), Digant Nayak (2,3), Scott J. Snipas (5), Farid El Oualid (6), Tony T. Huang (3,†), Miklos Bekes (7,†,‡), Marcin Drag (1,5,†), Shaun K. Olsen (2,3,†)

(1) Wroclaw University of Science and Technology, Poland. (2) Medical University of South Carolina, Charleston, USA. (3) University of Texas Health Science Center at San Antonio, San Antonio, USA. (4) New York University School of Medicine, New York, USA. (5) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA. (6) UbiQ Bio B.V., Amsterdam, The Netherlands. (7) Independent Consultant. (*) These authors contributed equally to this work. (†) Corresponding author. (‡) Present address: Arvinas Inc., New Haven, USA.

Science Advances 2020, Vol. 6, no. 42, eabd4596. DOI: 10.1126/sciadv.abd4596
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