Project 4: Nuclease Inhibitors for Viruses of Pandemic Concern

Nuclease Inhibitors for Viruses of Pandemic Concern, SARS-CoV-2 (left) and Lassa virus (right) ExoN engaging the RNA substrate, — SARS-CoV-2 (left) and Lassa virus (right) ExoN engaging the RNA substrate

Image Credit: Yang Yang

Reference: (Left) Liu et al., Science (2021) Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme. (Right) Jiang et al., JBC (2013) Structures of Arenaviral Nucleoproteins with Triphosphate dsRNA Reveal a Unique Mechanism of Immune Suppression.

Project Description

Exons are enzymes and part of RNA that codes for proteins. SARS-CoV-2 and highly pathogenic arenaviruses share a structurally and functionally related exon domain. Exons play essential roles in proofreading viral RNA synthesis and suppressing antiviral responses.

Project 4 is aimed at the chemical inhibition of the exon function of these viruses. Our team has contributed extensively to the structural and functional understanding of these viral exon enzymes, including the understanding of their atomic structures and mechanisms. Building on our prior studies, we use three complementary approaches (ultra-high throughput screening, DNA-encoded technology and virtual screening) to identify first-in-class viral exon inhibitors.

We aim to discover a new class of antiviral drug candidates with a distinct mechanism of action to complement or enhance those developed against other viral targets. In addition, our work will address the critical need for novel therapeutics against SARS-CoV-2 and the highly pathogenic arenaviruses that causes fatal human hemorrhagic fever infections.

Active-site conformation and catalytic mechanism of SARS-CoV-2 ExoN

Principal Investigator

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

[email protected]

Deputy Investigator

yuying liang, nuclease inhibitor, university of minnesota, Midwest AVidd, Pandemic, virology, virus, covid-19 — **Yuying Liang, Ph.D**

[email protected]

Deputy Investigator

Hinh Ly, University of minnesota, Nuclease inhibitor, sars-cov2, Covid-19, Lassa, Zika, Viral replication — **Hinh Ly, Ph.D**

[email protected]

yang yang, university of iowa, virology, nuclease inhibitors, midwest avidd, minnesota, pandemic, genius, sars, ebola, zika — **Yang Yang, Ph.D: Iowa State University**

[email protected]

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

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Robert Davey, Gain-of-function, Animal testing, pathogenesis, University of Boston, Lab leak — **Robert Davey, Ph.D: Boston University, OSC**

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Martin Matzuk, M.D., Ph.D: Baylor University, OSC, midwest AViDD, covid, antiviral, immunology, pediatrics, — **Martin Matzuk, M.D., Ph.D: Baylor University, OSC**

[email protected]

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

[email protected]

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, OSC**

[email protected]

SARS-CoV-2 (left) and Lassa virus (right) ExoN engaging the RNA substrate

Active-site conformation and catalytic mechanism of SARS-CoV-2 ExoN

Principal Investigator

Hideki Aihara, Ph.D

Deputy Investigator

Deputy Investigator

Co-Investigators and Other Significant Contributors (OSC)