Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development

Abstract

SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.

SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery

“…These tubercidin-derived compounds are less cytotoxic and decrease the activity of nsp16 in biochemical assays (Klima et al 2022; Schultz et al 2022; Li et al 2023) and in the case of SS148 also the activity of nsp14 (Devkota et al 2021). Despite the knowledge of binders and inhibitors together with diverse in silico drug screens (Xu et al 2020; Maurya et al 2020; El Hassab et al 2021; Vijayan et al 2020) and an NMR fragment screen (Berg et al 2022), no selective and effective nsp16 inhibitor has been identified to this point. Crystal structures of nsp10-16 from SARS-CoV, SARS-CoV-2, and MERS-CoV are available (Wilamowski et al 2021; Chen et al 2011, e.g.…”

NMR characterization and ligand binding site of the stem loop 2 motif (s2m) from the Delta variant of SARS-CoV-2

“…Both strategies, while being effective, inevitably tend to be sensitive towards evolutionary pressure to evade the immune response or the antiviral agent. To provide a broader approach, our project Covid19-nmr (Duchardt-Ferner et al 2023), has focused on screening the entire proteome (Berg and Wirtz Martin and Altincekic et al 2022) and RNA genome of SCoV-2 to identify binding fragments for further medicinal chemistry campaigns. One underestimated but promising research area is the development of drugs targeting RNA, which could potentially revolutionize antiviral treatment.…”