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A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors*.
Yang, Kai S; Ma, Xinyu R; Ma, Yuying; Alugubelli, Yugendar R; Scott, Danielle A; Vatansever, Erol C; Drelich, Aleksandra K; Sankaran, Banumathi; Geng, Zhi Z; Blankenship, Lauren R; Ward, Hannah E; Sheng, Yan J; Hsu, Jason C; Kratch, Kaci C; Zhao, Baoyu; Hayatshahi, Hamed S; Liu, Jin; Li, Pingwei; Fierke, Carol A; Tseng, Chien-Te K; Xu, Shiqing; Liu, Wenshe Ray.
  • Yang KS; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Ma XR; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Ma Y; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Alugubelli YR; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Scott DA; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Vatansever EC; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Drelich AK; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Sankaran B; Molecular Biophysics and Integrated Bioimaging Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Geng ZZ; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Blankenship LR; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Ward HE; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Sheng YJ; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Hsu JC; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Kratch KC; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Zhao B; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • Hayatshahi HS; Department of Pharmaceutical Sciences, UNT Health Science Center, Fort Worth, TX 76107, USA.
  • Liu J; Department of Pharmaceutical Sciences, UNT Health Science Center, Fort Worth, TX 76107, USA.
  • Li P; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • Fierke CA; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
  • Tseng CK; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
  • Xu S; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Liu WR; Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
ChemMedChem ; 16(6): 942-948, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-959133
ABSTRACT
The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro ), we have designed and synthesized a series of SC2MPro inhibitors that contain ß-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 µM and A549/ACE2 cells at 0.16-0.31 µM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2021 Document Type: Article Affiliation country: Cmdc.202000924

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2021 Document Type: Article Affiliation country: Cmdc.202000924