Drug repurposing screen to identify inhibitors of the RNA polymerase (nsp12) and helicase (nsp13) from SARS-CoV-2 replication and transcription complex

Maria Kuzikov

;Jeanette Reinshagen;Krzysztof Wycisk;Angela Corona;Francesca Esposito;Paolo Malune;Candida Manelfi;Daniela Iaconis;Andrea Beccari;Enzo Tramontano;Marcin Nowotny;Bjorn Windshügel;Philip Gribbon;Andrea Zaliani

2024-01-01

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Abstract

Coronaviruses contain one of the largest genomes among the RNA viruses, coding for 14–16 non-structural proteins (nsp) that are involved in proteolytic processing, genome replication and transcription, and four structural proteins that build the core of the mature virion. Due to conservation across coronaviruses, nsps form a group of promising drug targets as their inhibition directly affects viral replication and, therefore, progression of infection. A minimal but fully functional replication and transcription complex was shown to be formed by one RNA-dependent RNA polymerase (nsp12), one nsp7, two nsp8 accessory subunits, and two helicase (nsp13) enzymes. Our approach involved, targeting nsp12 and nsp13 to allow multiple starting point to interfere with virus infection progression. Here we report a combined in-vitro repurposing screening approach, identifying new and confirming reported SARS-CoV-2 nsp12 and nsp13 inhibitors.