Project 3: Pandemic Virus Protease Inhibitors

Schematic of SARS-CoV-2 main protease in complex with inhibitor, Project 3: Pandemic Virus Protease Inhibitors — Schematic of SARS-CoV-2 main protease in complex with inhibitor CDD-1713 (image derived from x-ray structure PDB ID 7LTN; Chamakuri *et al*., 2022, *PNAS*, PMID: 34426525).

Project Description

The proteases of SARS-CoV-2 are scissor-like enzymes that precisely cut longer viral protein precursors into functional units required for pathogenesis.

Project 3 of the Midwest AviDD Center is developing chemical inhibitors of the main SARS-CoV-2 protease, Mpro, which is required for 11 distinct cutting events that are all required for virus replication. This enzyme is therefore an excellent drug target as demonstrated by the clinical protease inhibitor, Paxlovid (Pfizer), and other potent drugs developed for other viral proteases including those of HIV-1 and HCV.

However, additional Mpro inhibitors are required to combat the inevitable problem of viral variants that become resistant to drug treatment. Several such variants already exist in the human population, and, over time, these rare isolates may become more frequent and undermine the efficacy of Paxlovid and other drugs in development.

The Project 3 team is therefore using a combination of traditional and innovative screening strategies to identify and validate new Mpro inhibitors. Top candidates are then developed further in close collaboration with chemistry, structural biology, and virology teams. In addition to many training opportunities, the major deliverable from this work will be new inhibitors of this essential viral enzyme that can be collaboratively developed into next-generation drugs.

Project 3 is also utilizing similar approaches to target the essential protease of Zika virus, which is another virus with pandemic potential.

SARS-CoV-2 Mpro hits, analogs and examples of enzymatic inhibitory activity of these key molecules

Project 3: Pandemic Virus Protease Inhibitors — (A) Active and inactive small molecules synthesized off DNA are shown. (B) Inhibition value determination against Mpro with a concentration-dependent inhibition curve.

Principal Investigator

howard hughes, protease inhibitor, Reuben Harris, Fang Li, Midwest AViDD, Midwest Antiviral Drug Discovery Center, Drug development — **Reuben Harris, Ph.D**

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Deputy Investigator

Lanying Du, Ph.D: Georgia State University, lab leak, covid-19, wuhan — **Lanying Du, Ph.D**

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Deputy Investigator

Damian Young, Ph.D, baylor, protease inhibitors, protein, covid-19, midwest Avidd, antiviral, pandemic — **Damian Young, Ph.D**

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Hideki Aihara, Ph.D: University of Minnesota, project 4: nuclease, AViDD, Midwest Antiviral Drug Discovery Center, Coronavirus research center — **Hideki Aihara, Ph.D: University of Minnesota**

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Louis Scampavia, Ph.D: UF Scripps, high-throughput screening, small molecule discovery, drug design, antiviral, Midwest AViDD, pandemic, virology, covid-19 — **Louis Scampavia, Ph.D: UF Scripps**

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Rommie Amaro, Amaro Lab, Covid-19, Midwest AViDD, Midwest Antiviral Drug Discovery Center, — **Rommie Amaro, Ph.D: UC San Diego**

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Ryan Langlois, Ph.D: University of Minnesota, OSC, animal testing, virology, antiviral, vaccines, Midwest Avidd, in vitro, disease, pathology, mutations — **Ryan Langlois, Ph.D: University of Minnesota, OSC**

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**Timothy Palzkill, Ph.D: Baylor College of Medicine, OSC**

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Daniel Harki, Midwest AViDD, Protease inhibitors, University of Minnesota, virology — **Daniel Harki, Ph.D: University of Minnesota**

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Michael Farzan, UF Scripps Biomedical Research, Lab Leak, Covid-19, Project 1: Small Molecule Entry Inhibitors of Pandemic Viruses — **Michael Farzan, Ph.D: UF Scripps, OSC**

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Dahai Luo, Nanyang technical university singapore, Core C, Computational Virology, Ming Luo, Project 1, Small Molecule inhibitors, Georgia State University — **Dahia Luo, Ph.D: Nanyang Technical University, Singapore, OSC**

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Teresa Head-Gordon, Ph.D: UC Berkeley, midwest Avidd, drug discovery antiviral — **Teresa Head-Gordon, Ph.D: UC Berkeley**

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Kang Congbao, Singapore, drug testing, drug discovery, sars, covid-19, — **Kang Congbao Ph.D: A*Star, OSC**

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SARS-CoV-2 Mpro hits, analogs and examples of enzymatic inhibitory activity of these key molecules

Principal Investigator

Deputy Investigator

Deputy Investigator

Co-Investigators and Other Significant Contributors (OSC)

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