Fragment-based drug discovery of SARS-CoV-2 methyltransferase nsp14 inhibitors Anna Lina Bula, Iveta Kanepe, Diana Zelencova-Gopejenko, Laura Drunka, Kristaps Jaudzems Latvian Institute of Organic Synthesis, Latvia The Covid-19 pandemic, caused by the highly infectious SARS-CoV-2, has highlighted the urgent need to create effective antiviral therapies. The nonstructural protein 14 (nsp14) is a key component of the viral replication machinery. It is an S-adenosylmethionine-dependent guanine-N7 methyltransferase necessary for viral mRNA capping that ensures mRNA stability and translation, as well as host immune system evasion. It is therefore an appealing target for drug development. Using the DSI-poised library, we performed a ligand-observed NMR fragment screening of nsp14, specifically exploring the SAM binding pocket. The known SAM analog, sinefungin, was used in the competitive binding experiments. We identified 47 compounds that showed binding to nsp14, two of which were competitive binders. These fragments represent promising starting points for hit-to-lead optimization towards the development of potent and selective nsp14 inhibitors. This work was done as part of the Covid19-NMR consortium and was financially supported by the Latvian Council of Science, grant numbers:VPP-COVID-2020/1-0014 andVPP-EM-BIOMEDICĪNA-2022/1-0001. References 1. Y. Chen, et al. PNAS , 2009, vol. 106 (9 ), 3484-3489. 2. H. Berg, et al. Angew. Chem.Int.Ed. , 2022, vol. 134 (46) , 10.1002/ange.202205858.
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