Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants

Miaomiao Liu, Dene R. Littler, Jamie Rossjohn, Ronald J. Quinn

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7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7327-7332
Number of pages6
JournalACS Omega
Issue number8
Publication statusPublished - 1 Mar 2022

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