CABS Webinar: Targeting Coronaviral Proteases with Small Molecule Drugs

Date: March 16, 2020 @ 3:30 pm – @ 5:00 pm
Location: Zoom Conference

CABS Webinar

Targeting Coronaviral Proteases with Small Molecule Drugs  

US Pacific Time: March 16 (Monday), 2020. 3:30PM-5:00PM

China Beijing Time: March 17 (Tuesday), 2020, 6:30AM-8:00AM

Please click the link below to join the webinar:
From US: https://zoom.us/j/930185112

From China: https://zoom.com.cn/j/930185112

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Webinar ID: 930 185 112
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Agenda

(This event will be broadcast to you through Zoom Conference; agenda is based on US Pacific Time)

3:30 pm - 3:40 pm Introduction to CABS, Yang Tian, President of CABS

3:40 pm - 4:40 pm Targeting Coronaviral Proteases with Small Molecule Drugs, Andrew Mesecar, PhD, Head of Biochemistry Department, Purdue University

4:40 pm - 5:00 pm Q&A

Speaker

Andrew Mesecar is the Walther Professor of Structural Biology and Head of the Department of Biochemistry at Purdue University.  He also serves as the Deputy Director of the Purdue Center for Cancer Research. After the SARS outbreak in 2004, his lab started working on the discovery and structure-based design of inhibitors that target coronavirus 3C-like and papain-like proteases (PLpro) for the development of antiviral agents and attenuated vaccines.  Working with Susan Baker at Loyola University, they were the first to discover that coronavirus papain-like proteases also function as deubiquitinating and deISGylating enzymes and that the structures of coronavirus papain-like protease domains are almost identical to the 58 known human ubiquitin specific proteases (USPs). In collaboration with his colleague Dr. Arun Ghosh (Purdue University), inventor of the FDA approved HIV protease drug Darunavir (Prezista®), his team has shown that coronaviral proteases (Plpro and 3CLpro) can be potently inhibited with small molecule compounds. They have developed a series of potent and selective PLpro inhibitors that are capable of inhibiting SARS-CoV in vitro and in a designed BSL2 animal model system.  In addition, his team has developed a series of broad-spectrum inhibitors that inhibit the 3CLpro enzyme from over 11 different coronaviruses.  They are currently testing their inhibitors and HIV and HCV protease inhibitors against  PLpro and 3CLpro from SARS-CoV-2 that causes COVID-19.  His studies support that these two proteases are viable drug targets and that their compounds may serve one day to treat coronavirus infections. Professor Mesecar has has authored over 135 peer-reviewed scientific publications and he has presented his research in over 150 seminars and poster presentations.  His research is currently funded by grants from the National Institutes of Health and  the Walther Cancer Foundation.

Webinar Abstract

Human coronaviruses such as SARS-CoV, MERS and SARS-CoV-2 continue to emerge as significant threats to public health. Other human coronaviruse such as NL63, HKU1, 229E and OC43 continue to persist in the population but are significantly less deadly. Due to the lack of any approved therapeutics for coronaviruses, the development of both vaccines and anti-viral drugs is paramount.  HIV and HCV antiviral drug development teaches us that no single drug or class of drug target will suffice - we need multiple drugs in our arsenal to treat these diseases. The flu virus reminds us each year that we need to have both vaccines and small-molecule drugs available to control this deadly virus.  Since the SARS-CoV epidemic emerged in 2003, we have worked to develop small-molecule inhibitors of coronavirus 3C-like protease (3CLpro) and the papain-like protease (PLP or PLpro). Initially, we focused on the proteases from SARS and then on NL63 and MERS.  However, the differences in inhibitory potencies of our compounds and the taxonomic distance of the alpha and beta coronavirus genera taught us that approach of studying one virus at a time was too slow and provided to little molecular information to inhibit multiple coronaviruses. Moreover, it was not allowing us to predict how to inhibit emerging coronavirus pathogens.  In the interest of pandemic preparedness, we are now taking what we call a taxonomically-driven approach to the structure-based design of coronavirus protease inhibitors.  We targeted 3CLpro from the alpha-, beta- and gamma-coronavirus genera (FIPV, PEDV, NL63, HKU1, OC43, SARS, HKU4, HKU5, HKU9 and IBV) with a series of 50 compounds that we designed and synthesized using the Automated Synthesis and Purification platform at Eli Lilly.  We identified inhibitor templates that potently inhibit the enzymes from the alpha and beta genera but not the gamma genus. To ascertain the structural basis of the selectivity, we used X-ray crystallography and a sparse-matrix sampling approach and determined multiple X-ray structures of 3CLpro in complex with different inhibitors from multiple CoVs. We have identified precise regions in the structures that define selectivity and we have extended this approach to PLpro.


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