tetano
Editor, Senior Moderator
Am J Cancer Res
. 2020 Aug 1;10(8):2535-2545.
eCollection 2020.
Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug
Yu-Chuan Wang[SUP] 1 [/SUP], Wen-Hao Yang[SUP] 2 [/SUP], Chia-Shin Yang[SUP] 1 [/SUP], Mei-Hui Hou[SUP] 1 [/SUP], Chia-Ling Tsai[SUP] 1 [/SUP], Yi-Zhen Chou[SUP] 1 [/SUP], Mien-Chie ****[SUP] 2 3 4 [/SUP], Yeh Chen[SUP] 1 3 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), took tens of thousands of lives and caused tremendous economic losses. The main protease (M[SUP]pro[/SUP]) of SARS-CoV-2 is a potential target for treatment of COVID-19 due to its critical role in maturation of viral proteins and subsequent viral replication. Conceptually and technically, targeting therapy against M[SUP]pro[/SUP] is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M[SUP]pro[/SUP] inhibitor, efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), porcine epidemic diarrhea virus (PEDV), and feline infectious peritonitis virus (FIPV). Due to the conservation of structure and catalytic mechanism of coronavirus main protease, repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment of COVID-19 in humans. To validate this conjecture, the binding affinity and IC[SUB]50[/SUB] value of M[SUP]pro[/SUP] with GC376 was determined by isothermal titration calorimetry (ITC) and fluorescence resonance energy transfer (FRET) assay, respectively. The results showed that GC376 binds to SARS-CoV-2 M[SUP]pro[/SUP] tightly (K[SUB]D[/SUB] = 1.6 μM) and efficiently inhibit its proteolytic activity (IC[SUB]50[/SUB] = 0.89 μM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M[SUP]pro[/SUP] in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M[SUP]pro[/SUP] covalently linked through forming a hemithioacetal group and releasing a sulfonic acid group. Because GC376 is already known as a broad-spectrum antiviral medication and successfully used in animal, it will be a suitable candidate for anti-COVID-19 treatment.
Keywords: COVID-19; SARS-CoV-2; coronavirus (CoV); drug action; drug development; drug screening; protease inhibitor; structural biology.
. 2020 Aug 1;10(8):2535-2545.
eCollection 2020.
Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug
Yu-Chuan Wang[SUP] 1 [/SUP], Wen-Hao Yang[SUP] 2 [/SUP], Chia-Shin Yang[SUP] 1 [/SUP], Mei-Hui Hou[SUP] 1 [/SUP], Chia-Ling Tsai[SUP] 1 [/SUP], Yi-Zhen Chou[SUP] 1 [/SUP], Mien-Chie ****[SUP] 2 3 4 [/SUP], Yeh Chen[SUP] 1 3 [/SUP]
Affiliations
- PMID: 32905393
- PMCID: PMC7471349
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), took tens of thousands of lives and caused tremendous economic losses. The main protease (M[SUP]pro[/SUP]) of SARS-CoV-2 is a potential target for treatment of COVID-19 due to its critical role in maturation of viral proteins and subsequent viral replication. Conceptually and technically, targeting therapy against M[SUP]pro[/SUP] is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M[SUP]pro[/SUP] inhibitor, efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), porcine epidemic diarrhea virus (PEDV), and feline infectious peritonitis virus (FIPV). Due to the conservation of structure and catalytic mechanism of coronavirus main protease, repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment of COVID-19 in humans. To validate this conjecture, the binding affinity and IC[SUB]50[/SUB] value of M[SUP]pro[/SUP] with GC376 was determined by isothermal titration calorimetry (ITC) and fluorescence resonance energy transfer (FRET) assay, respectively. The results showed that GC376 binds to SARS-CoV-2 M[SUP]pro[/SUP] tightly (K[SUB]D[/SUB] = 1.6 μM) and efficiently inhibit its proteolytic activity (IC[SUB]50[/SUB] = 0.89 μM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M[SUP]pro[/SUP] in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M[SUP]pro[/SUP] covalently linked through forming a hemithioacetal group and releasing a sulfonic acid group. Because GC376 is already known as a broad-spectrum antiviral medication and successfully used in animal, it will be a suitable candidate for anti-COVID-19 treatment.
Keywords: COVID-19; SARS-CoV-2; coronavirus (CoV); drug action; drug development; drug screening; protease inhibitor; structural biology.