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

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

doi:10.1021/acsomega.1c07186

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

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

Research output: Contribution to journal › Article › Research › peer-review

10 Citations (Scopus)

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.

Original language	English
Pages (from-to)	7327-7332
Number of pages	6
Journal	ACS Omega
Volume	7
Issue number	8
DOIs	https://doi.org/10.1021/acsomega.1c07186
Publication status	Published - 1 Mar 2022

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title = "Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants",

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.",

author = "Miaomiao Liu and Littler, {Dene R.} and Jamie Rossjohn and Quinn, {Ronald J.}",

note = "Funding Information: This research was funded by the Australian Research Council Linkage Project (LE120100170). J.R. is supported by an Australian Research Council Laureate Fellowship. Publisher Copyright: {\textcopyright} 2022 The Authors. Published by American Chemical Society",

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AU - Rossjohn, Jamie

AU - Quinn, Ronald J.

N1 - Funding Information: This research was funded by the Australian Research Council Linkage Project (LE120100170). J.R. is supported by an Australian Research Council Laureate Fellowship. Publisher Copyright: © 2022 The Authors. Published by American Chemical Society

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

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