tetano
Editor, Senior Moderator
ACS Pharmacol Transl Sci
. 2021 Jun 9;4(4):1408-1421.
doi: 10.1021/acsptsci.1c00099. eCollection 2021 Aug 13.
Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir
Zilei Xia[SUP] 1 [/SUP], Michael Sacco[SUP] 2 [/SUP], Yanmei Hu[SUP] 1 [/SUP], Chunlong Ma[SUP] 1 [/SUP], Xiangzhi Meng[SUP] 3 [/SUP], Fushun Zhang[SUP] 3 [/SUP], Tommy Szeto[SUP] 1 [/SUP], Yan Xiang[SUP] 3 [/SUP], Yu Chen[SUP] 2 [/SUP], Jun Wang[SUP] 1 [/SUP]
Affiliations
Abstract
SARS-CoV-2 main protease (M[SUP]pro[/SUP]) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M[SUP]pro[/SUP] is highly conserved among all seven human coronaviruses, with certain M[SUP]pro[/SUP] inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 M[SUP]pro[/SUP] with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the M[SUP]pro[/SUP]'s from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M[SUP]pro[/SUP] assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 M[SUP]pro[/SUP]. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M[SUP]pro[/SUP] with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broad-spectrum coronavirus antivirals.
. 2021 Jun 9;4(4):1408-1421.
doi: 10.1021/acsptsci.1c00099. eCollection 2021 Aug 13.
Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir
Zilei Xia[SUP] 1 [/SUP], Michael Sacco[SUP] 2 [/SUP], Yanmei Hu[SUP] 1 [/SUP], Chunlong Ma[SUP] 1 [/SUP], Xiangzhi Meng[SUP] 3 [/SUP], Fushun Zhang[SUP] 3 [/SUP], Tommy Szeto[SUP] 1 [/SUP], Yan Xiang[SUP] 3 [/SUP], Yu Chen[SUP] 2 [/SUP], Jun Wang[SUP] 1 [/SUP]
Affiliations
- PMID: 34414360
- PMCID: PMC8204911
- DOI: 10.1021/acsptsci.1c00099
Abstract
SARS-CoV-2 main protease (M[SUP]pro[/SUP]) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M[SUP]pro[/SUP] is highly conserved among all seven human coronaviruses, with certain M[SUP]pro[/SUP] inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 M[SUP]pro[/SUP] with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the M[SUP]pro[/SUP]'s from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M[SUP]pro[/SUP] assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 M[SUP]pro[/SUP]. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M[SUP]pro[/SUP] with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broad-spectrum coronavirus antivirals.