4.5 Article

Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate

Journal

ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 7, Pages 1102-1107

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00140

Keywords

SARS-CoV-2; MTase inhibitors; Nsp14; Nsp16; SAM analogues; antiviral drugs

Funding

  1. Latvian Council of Science [VPP-COVID-2020/1-0014]
  2. European Regional Development Fund [1.1.1.2/VIAA/4/20/747, 1.1.1.2/VIAA/2/18/379]

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This study designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the cosubstrate SAM. Testing showed good inhibitory activity of five compounds. However, poor cell permeability was observed for all evaluated compounds.
Viral mRNA cap methyltransferases (MTases) are emerging targets for the development of broad-spectrum antiviral agents. In this work, we designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the sulfonium and amino acid substructures of the cosubstrate S-adenosylmethionine (SAM), which serves as the methyl donor in the enzymatic reaction. The synthetically accessible target structures were prioritized using molecular docking. Testing of the inhibitory activity of the synthesized compounds showed nanomolar to submicromolar IC50 values for five compounds. To evaluate selectivity, enzymatic inhibition of the human glycine N-methyltransferase involved in cellular SAM/SAH ratio regulation was also determined, which indicated that the discovered compounds are nonselective inhibitors of the studied MTases with slight selectivity for Nsp16. No cytotoxic effects were observed; however, this is most likely a result of the poor cell permeability of all evaluated compounds.

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