Uncovering novel drug targets of polyprotein precursors of SARS-CoV2
The current COVID-19 pandemic is caused by a novel coronavirus SARS-CoV2 (Severe Acute Respiratory syndrome-coronavirus 2). In spite of earlier outbreaks of similar coronaviruses such as, SARS-CoV and MERS-CoV, an effective therapeutic solution is not yet available for SARS-CoV2. Efforts to develop therapeutic agents to combat the spread of COVID-19 and to tackle any future pandemic outbreaks are thus urgent. In this light, we propose a project targeting structural domains of the non-structural polyprotein 3 (Nsp3) of SARS-CoV2 as important therapeutic foci. Nsp3 is a polyprotein precursor containing 15 individual domains, which, when auto-cleaved, are crucial to the function and life cycle of SARS-CoV2. The N-terminal proteins of Nsp3 are cleaved by a viral papain-like protease, PLpro.
Immediately upstream and downstream of PLpro, lie an ubiquitin-binding domain, Ubl2 and a nucleic-acid binding domain, NAB, followed by a beta-CoV specific marker region (βSM), respectively. Unlike the classical approach of studying these potential drug targets as individual domains, this project aims at structural and functional studies of PLpro in the polyprotein context, targeting Nsp3 Ubl2-PLpro-NAB, and Ubl2-PLpro-NAB-βSM in order to explore novel small molecule binding sites that might provide new leads for antiviral therapeutics. The project will adopt a multi-level approach, in which molecular biology, X-ray and neutron structural methods will be combined with cryo-EM, thus integrating complementary techniques in modern structural biology.
Nuvisan ICB GmbH