image: From top left to bottom right: Yogesh Gupta, Luiza Mendonça, Ryan Abdella, Shaun Olsen, Elisa Fanunza, Shawn Yang and Tony Huang. view more
Credit: University of Minnesota.
MINNEAPOLIS/ST. PAUL (07/05/2023) – To accelerate the Midwest Antiviral Drug Discovery (AViDD) Center's mission to develop therapeutics for viruses with pandemic potential, the Center today announced $3 million in funding for six additional projects over the next two years.
The projects will expand the Center's expertise across disciplines to discover effective responses to pandemics, life-threatening infections, and antiviral resistance through basic and translational research. Equally important, the funding helps fulfill the Center’s mission to produce well-trained groups of antiviral researchers that will be the next generation of experts and leaders.
“It is very important that the virology community continue to foster the development of expert scientists, who can help contribute to vanquishing SARS-CoV-2 and, most importantly, be better prepared to aggressively fight the next pandemic,” said Reuben Harris, PhD, co-director of the Midwest AViDD Center.
The Midwest AViDD Center received numerous applications for funding from around the globe, which resulted in a highly competitive process. Grant applications were ranked by the Center's Executive Leadership Team and Scientific Advisory Board. Final funding decisions were made by the National Institute of Allergy and Infectious Diseases.
Developmental Research Projects
Discovery of novel SARS-CoV-2 papain-like protease (PLpro) small molecule inhibitors for future COVID-19 antiviral development
Shaun Olsen, PhD (University of Texas Health Science Center at San Antonio) and Tony Huang, PhD (NYU Grossman School of Medicine).
Most protease inhibition research has focused on SARS-CoV-2 main protease (Mpro). This project focuses on PLpro, the other essential protease involved with SARS-CoV-2 viral replication. Currently, there are no clinical drugs that work against PLpro. The project will collaborate with Midwest AViDD Center Project 3 and use Core B’s High-Throughput Screening and DNA-Encoded Chemistry Technology (DEC-Tec) capabilities. Previously, the collaboration between Olsen and Huang yielded the first SARS-CoV-2 PLpro crystal structure during the early days of the pandemic.
Targeting novel nsp16/nsp10 surfaces for efficient blocking of 2’-O methylation of SARS-CoV-2 mRNA
Yogesh Gupta, PhD (University of Texas Health Science Center at San Antonio).
Gupta studies how the nsp16-nsp10 enzyme complex of SARS-CoV-2 modifies and shields its messenger RNA to hide inside host cells. The resulting viral RNA mimics the host RNAs, subverts the host's immune response, and helps the virus hijack the host's protein synthesis machinery. Gupta's work has discovered new critical features of this mechanism that novel small molecules can selectively block.
Mentored Projects
Structure-guided inhibition of Lassa virus nucleoprotein interactions with polymerase and RNA
Ryan Abdella, PhD (University of Minnesota).
Abdella will be mentored by Hideki Aihara (U of M) for his project. The project is an ambitious undertaking to characterize the structures of critical viral proteins involved in the replication of the Lassa virus and to develop antivirals to treat an endemic disease that kills over 5,000 annually in sub-Saharan Africa.
In-situ High-resolution Imaging of the Effects of Novel Antivirals
Luiza Mendonça, PhD (University of Minnesota).
Mendonça will determine an antiviral mechanism of action, validate its structure, and investigate the toxicity of compounds produced by the Midwest AViDD Center. The cryo imaging of virus-infected cells treated with compounds using cryotomography will be essential for a compound to advance to the candidate drug stage. Mendonça is mentored by Harris and Hinh Ly (U of M).
Inhibitors of Lassa Virus Endonuclease
Shawn Yang, PhD (Georgia State University).
Yang will also investigate the Lassa virus and be mentored by Binghe Wang and Ming Luo (GSU). The project seeks to create an inhibitor that inhibits the endonuclease activity in the Lassa virus. When endonuclease activity is halted, viral transcription is blocked, and viral replication is terminated. The project is a novel supplement to existing programs within the Center. Encouragingly, the FDA has approved other drugs targeting a virus's endonuclease, most notably for influenza.
Targeting SARS-CoV-2 Endoribonuclease Nsp15
Elisa Fanunza, PhD (University of Cagliari).
Fanunza will focus on discovering therapeutics for SARS-CoV-2 directed against a less-conventional but attractive target, Nsp15, a virus-encoded endonuclease essential for pathogenesis and evading host immunity. The research aims to deliver direct Nsp15-targeting antivirals that block endonuclease activity and restore host innate immune responses. Fanunza is mentored by Harris and Enzo Tramontano, PhD (University of Cagliari).
This research and the Midwest AViDD Center are supported by the National Institute of Allergy and Infectious Diseases (U19-AI171954).
-30-
About the Midwest AViDD Center
The Midwest AViDD Center is developing the next generation of antiviral drugs for pandemic-level viruses, including SARS-CoV-2, Ebola, Lassa, and Zika. Headquartered at the University of Minnesota and including 18 other institutions nationwide, the Midwest AViDD Center is part of a network of nine national centers established by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.