California Center for Antiviral Drug Discovery
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The state of California is severely impacted by a number of viral pathogens and emerging diseases. The RNA viruses, hepatitis C, HIV, Dengue, SARS-Coronavirus, and rhinoviruses are serious state problems. For HIV the emergence of drug-resistant virus is significant. Little progress has been made with treatment for hepatitis C or the other viruses noted above. There is a need for a concerted academic drug discovery effort targeting these five RNA viruses. We propose a center within the University of California to achieve this goal. The approach will be multipronged, making use of key strengths across three UC campuses (UCI, UCLA, and UCSF). Center members include: WE Robinson, Jr, R Andino, M Buchmeier, AR Chamberlin, A Dasgupta, AD Frankel, T Poulos, BL Semler, GA Weiss, and J Zack. These investigators bring expertise in drug discovery, assay development, RNA virology, drug resistance, chemistry, x-ray crystallography, and animal models to the Center. First, we will employ a structure-based approach, relying on x-ray crystallography of inhibitor-resistant HIV integrase as well as the RNA-dependent RNA polymerase proteins of rhinovirus, hepatitis C virus, dengue virus, and SARS-coronavirus. Next, we will screen for compounds with inhibitory activity against each protein. Screening will include antiviral activity against each protein, co-crystallization with each compound, and antiviral activity in tissue culture. Compounds will be derived from a panel of existing natural products and from small compound libraries. As compounds are identified, they will be studied in mouse models of HIV infection and, when practical, animal models of rhinovirus and flavivirus infection. Central to these studies will be the following long range aims: 1. Develop high through-put cytolytic assays for screening viral replication inhibitors. 2. Screen natural product libraries and generate small, combinatorial synthetic libraries for inhibitors of RNA virus replication based upon lead compounds identified in natural products. 3. Develop sensitive and quantitative measures of viral RNA replication within infected cell cultures. 4. Determine the effects of compounds with antiviral properties on in vitro RNA replication. 5. Synthesize drug-like molecules based on lead compounds directed at bona fide RNA replication targets. 6. Utilize protein structure platforms to identify optimum candidate anti-viral compounds, and optimize compound structure through iterative synthesis. 7. Develop novel protein-protein interaction studies through the use of phage display technologies to identify new protein targets. 8. Optimize or develop candidate animal models using SCID-human reconstituted mice for preclinical animal studies. Once successful, we will partner with the private sector to complete pre-clinical and clinical development of candidate drugs. In addition to research there will be ample training opportunities for UC graduate and undergraduate students.