NECESSITY – New chemical entities for modulating SARS-CoV2 activity. A new Pipeline Strategy for Straightforward Structure Driven Drug Discovery targeting SARS-CoV2 reproduction.

• Applicant: Dr. Manfred S. Weiss, since 12/2021
• Subject Area: Structural Biology ; Biochemistry ; Virology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465064778

The world is plagued by the COVID-19 pandemic, leading to extensive human health concerns and global socio-economic disruption. The infectious disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), spreading rapidly worldwide. During the first year, SARS-CoV2 caused more than 66 million infections and more than 1.5 million deaths to date. Global scientific efforts are conducted to develop different vaccines and distinct therapeutic agents. While the former is close to distribution to the public, no distinct SARS-CoV2 neutralizing agent is reported to date. The current therapy of severe cases is essentially limited to administering steroid drugs to control the immune response and supply artificial respiration.This project focuses on repurposing small-molecule compounds and peptide-analogs – initially designed as kinase- and protease inhibitors - to neutralize SARS-CoV2. Amongst the inherent non-structural proteins for the viral life cycle, the main protease (Mpro, hereafter) is the primary target in this project. The proposed framework workflow is not restricted to this target, as it is expandable to address other viral proteins. We propose to screen a unique proprietary collection of 8000+ compounds containing scaffolds typically not existing in commercial libraries by high-throughput X-ray crystallography as the first selective step to identify potential Mpro binders. Identified hit compounds will be subjected to the different analysis routes simultaneously to examine their potential in all specific aspects, including preliminary virological studies. Established biophysical methods, e.g., MST, ITC, NMR, TSA, are used to determine binding modes and affinities, turnover rates, and HPLC-assays to dissect inhibitory effects. Applied biochemistry, designed to predict resistance mutations, provide insights towards likely protein mutations upon compound exposure. A patent-pending in-vitro selection assay analyzes the biological activity of chosen compounds. Consolidated data will translate into virological studies detailing each compound's possible modulating effect and or resistance mutation in-vivo.This novel and unique interdisciplinary trilateral workflow involves researchers from Medicinal University of Innsbruck, Austria, Helmholtz-Zentrum Berlin, Germany and University of Olomouc, Czech Republic. It is, utilizing drug-repurposing and translating into structure-guided optimization's evolutionary progress with selections of this unique proprietary library, including the possible synthetic optimization of new analogs. Verified by early-stage virological expertise, this novel approach maximizes success by combining structural data with biophysical, biochemical, and virological methods. This innovative interconnected multi-disciplinary approach is unique and opens the avenue to efficient substance characterization. It allows identifying anti-viral substances and the compound's activity in a very time-efficient manner.

• DFG Programme: Research Grants
• International Connection: Austria, Czech Republic
• Cooperation Partners: Professor Dr. Vladimir Krystof, Ph.D.; Professor Dr. Klaus Scheffzek
• Ehemaliger Antragsteller: Dr. Christian Feiler, until 12/2021