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Inhibition of the viral macrodomain as a strategy for Coronavirus treatment

Grant number: 20/05317-6
Support type:Regular Research Grants
Duration: July 01, 2020 - June 30, 2022
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Nicolas Carlos Hoch
Grantee:Nicolas Carlos Hoch
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Alexandre Bruni Cardoso ; Deborah Schechtman ; Flavia Carla Meotti
Associated research grant:18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health, AP.JP
Associated scholarship(s):20/11162-5 - Development of a cellular assay to measure SARS-CoV-2 Nsp3 macrodomain activity in vitro, BP.PD

Abstract

The search for anti-coronaviral treatments is largely focused on inhibitors of the viral polymerase or one of the viral proteases. However, the viral macrodomain contained in non-structural protein 3 (Nsp3) is an attractive and underexplored target, as it has a druggable catalytic pocket, is required for viral replication and is part of an important mechanism of active viral repression of the host interferon (IFN) response. These functions are mediated by the catalytic activity of this domain, which hydrolyzes (removes) a post-translational modification of proteins catalysed by enzimes that participate in the host anti-viral response, termed ADP-ribosylation, which is the subject of the current Young Investigator Award this application is linked to. We established a network of national and international collaborators in late March/early April 2020, with the purpose of searching for inhibitors of the SARS-CoV-2 macrodomain, starting with, but not limited to, an effort to repurpose currently approved drugs. The pipeline rapidly being implemented is composed of an initial virtual screening of compound libraries in silico, followed by biochemical assays to determine inhibition of recombinant SARS-CoV-2 macrodomain activity in vitro, co-crystalization of compounds with the viral domain, cellular assays to determine in vivo inhibition of the ectopically expressed viral macrodomain, as well as experiments on cells infected with either SARS-CoV-2 or other related coronaviruses to test anti-viral activity. This proposal encompasses the overall coordination of this effort, as well as the virtual screening and cellular assay development, and is therefore aimed at funding an important effort in the search for novel strategies of pharmacological treatments for COVID-19. (AU)