Targeting Functional RNA Elements in the SARS-CoV-2 Genome

Division Of Basic Sciences - Nci

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Abstract

Traditional drug screening strategies are based on targeting coronavirus-related proteins (e.g., RdRp, Mpro, and 3CLpro) and receptors (e.g. ACE2). In addition to virus-coded proteins, RNA structures within the SARS-CoV-2 genome also regulate essential functions and are potentially attractive and complementary targets for small molecules. RNA-targeting compounds would represent a highly novel approach for developing anti-SARS-CoV-2 therapeutics. The SARS-CoV-2 genome is a 29.9 kB, positive-sense, single-stranded RNA. Several regions within in the genome likely encode functions critical to virus replication. Here, we focus on two specific RNA elements, the frameshifting element (FSE) pseudoknot and the Stem-loop II-like motif (s2m) hairpin, both of which have been shown to form unique and stable three-dimensional structures. However, our efforts need not be limited to these structures: as continued information becomes available we aim to apply SMM screening to new structured regions of the SARS-CoV-2 genome as well. This proposal aims to discover drug-like small molecules that target functional elements within the SARS-CoV-2 genome as mechanistically novel antiviral compounds via a collaboration exploiting unique expertise of the participating labs.