Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants
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Littler, DR
Rossjohn, J
Quinn, RJ
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Abstract
SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we identified an ent-kaurane natural product, oridonin (1), with micromolar affinities. In this work, we have found that the prodrug HAO472 (2) directly binds to Nsp9, establishing replacement of the labile ester with a bioisostere as a candidate drug strategy. We further tested 1 and its clinical analogue 2 against two Nsp9 variants from human coronavirus 229E (HCoV-229E) and ferret systemic coronavirus F56 (FSCoV-F56). Both compounds showed significant binding selectivity to COVID-19 and HCoV-229E Nsp9 over FSCoV-F56 Nsp9, confirming the covalent bond with Cys73.
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ACS Omega
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7
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8
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© 2022 The Authors. Published by American Chemical Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND 4.0) License, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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Chemical engineering
Materials engineering
Macromolecular and materials chemistry
Physical chemistry
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Liu, M; Littler, DR; Rossjohn, J; Quinn, RJ, Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants, ACS Omega, 2021, 7 (8), pp. 7327-7332