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The Structure-Based Design of SARS-CoV-2 Nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

preprint
submitted on 22.02.2021, 14:57 and posted on 23.02.2021, 06:44 by Tomáš Otava, Michal Šála, Fengling Li, Jindřich Fanfrlík, Kanchan Devkota, Paknoosh Pakarian, Pavel Hobza, Masoud Vedadi, Evzen Boura, Radim Nencka
COVID-19, caused by the SARS-CoV-2 virus, is responsible for a global pandemic that has paralyzed the normal life in many countries around the globe. Therefore, the preparation of both effective vaccines and potential therapeutics has become a major research priority in the biotechnology sector. Both viral proteins and selected host factors are important targets for the treatment of this disease. Suitable targets for antiviral therapy include i.a. viral methyltransferases, which allow the viral mRNA to be efficiently translated and protect the viral RNA from the innate immune system. In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases, nsp14. This methyltransferase catalyzes the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to cap the guanosine triphosphate moiety of the newly synthesized viral RNA, yielding the methylated capped RNA and S-adenosyl-L-homocysteine (SAH). The crystal structure of SARS-CoV-2 nsp14 is unknown; we have taken advantage of its high homology to SARS-CoV nsp14 and prepared its homology model, which has allowed us to identify novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target. We have synthesized and tested the designed compounds in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme. The docking studies nicely explain the contribution of an aromatic part attached by a linker to the position 7 of the 7-deaza analogues of SAH. Our results will serve as an important source of information for the subsequent development of new antivirals to combat COVID-19.

Funding

European Regional Development Fund; OP RDE; Project: “Chemical Biology for Drugging Undruggable Targets (ChemBioDrug)” (No. CZ.02.1.01/0.0/0.0/16_019/0000729)

Ministry of Health of the Czech Republic, grant NU20-05-00472

Czech Academy of Sciences (RVO: 61388963)

Gilead Sciences Inc.

University of Toronto COVID-19 Action Initiative-2020 funds

The Structural Genomics Consortium is a registered charity (No: 1097737) receiving funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/ KTH, Diamond Innovative Medicines Initiative 2 Joint Under-taking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Merck & Co (aka MSD outside Canada and US), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome [106169/ZZ14/Z].

History

Email Address of Submitting Author

nencka@uochb.cas.cz

Institution

Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.

Country

Czech Republic

ORCID For Submitting Author

0000-0001-6167-0380

Declaration of Conflict of Interest

A part of the study was also supported by Gilead Sciences Inc.