Validation of putative SARS-CoV-2 macrodomain inhibitors obtained by virtual screening

• Grant number: 22/14895-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 03, 2023
• End date: July 02, 2024
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Nicolas Carlos Hoch
• Grantee: Isaac de Araujo Matos
• Supervisor: Ivan Ahel
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Oxford, England
• Associated to the scholarship: 21/10124-5 - Designing Sars-Cov-2 Mono-ADP-ribosyl hydrolase Enzyme Inhibitors: A New Class of Antiviral Agents?, BP.PD

Abstract

During viral infections, one of the strategies employed by the innate immune system is the so-called interferon response (IFN), which induces the expression of several anti-viral proteins to reduce viral replication and pathogenesis. This host response includes a class of enzymes called poly(ADP-ribose) polymerases (PARPs) that catalyse the post-translational modification of proteins with ADP-ribose units. This ADP-ribosylation has an important role against viral agents including the SARS-CoV-2 virus, either by amplifying the interferon signaling cascade or via direct anti-viral functions, such as degradation of viral nucleic acids and proteins. To counteract this activity, viral enzymes known as macrodomains catalyse the hydrolysis of this ADP-ribosylation, allowing viral replication and pathogenesis. Importantly, mutations in core residues required for macrodomain catalytic activity prevent coronavirus pathogenesis in mice, validating the coronavirus macrodomain as a promising molecular target for the development of new antiviral agents. In this context, this travel fellowship aims to thoroughly validate putative SARS-CoV-2 macrodomain inhibitors obtained by virtual screening, both for on-target activity on the viral macrodomain and for selectivity against human off-target enzymes of the same family. Finally, this proposal will allow collaboration between our group and that of Prof. Ivan Ahel, who is a world leader in the development of macrodomain inhibitors, in addition to fostering a partnership between the University of São Paulo and Oxford and consequently enabling the training of qualified human resources for the national implementation of robust bioassays. (AU)