tetano
Editor, Senior Moderator
ACS Omega
. 2022 Feb 15;7(8):7327-7332.
doi: 10.1021/acsomega.1c07186. eCollection 2022 Mar 1.
Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants
Miaomiao Liu[SUP] 1 [/SUP], Dene R Littler[SUP] 2 [/SUP], Jamie Rossjohn[SUP] 2 3 [/SUP], Ronald J Quinn[SUP] 1 [/SUP]
Affiliations
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.
. 2022 Feb 15;7(8):7327-7332.
doi: 10.1021/acsomega.1c07186. eCollection 2022 Mar 1.
Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants
Miaomiao Liu[SUP] 1 [/SUP], Dene R Littler[SUP] 2 [/SUP], Jamie Rossjohn[SUP] 2 3 [/SUP], Ronald J Quinn[SUP] 1 [/SUP]
Affiliations
- PMID: 35224406
- PMCID: PMC8862745
- DOI: 10.1021/acsomega.1c07186
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.