title: Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors.
abstract: Severe acute respiratory syndrome (SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CL(pro) of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R(1) or R(4) destabilizes the oxyanion hole in the 3CL(pro). Interestingly, 3f, 3g and 3m could inhibit both NA and 3CL(pro) and serve as a starting point to develop broad-spectrum antiviral agents.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Vathan
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Kian-Pin
authors.initials: KP
authors.lastname: Tan
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan. Electronic address: phliang@gate.sinica.edu.tw.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Liang
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D065207:Middle East Respiratory Syndrome Coronavirus / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: 3CL(pro); Coronavirus; MERS-CoV; Pyrazolone; SARS-Cov