title: Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CLProinhibitors.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory illness with fever, cough and shortness of breath. Up to date, it has resulted in 1826 human infections, including 649 deaths. Analogous to picornavirus 3C protease (3Cpro), 3C-like protease (3CLpro) is critical for initiation of the MERS-CoV replication cycle and is thus regarded as a validated drug target. As presented here, our peptidomimetic inhibitors of enterovirus 3Cpro(6b, 6c and 6d) inhibited 3CLproof MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV) with IC50values ranging from 1.7 to 4.7 μM and from 0.2 to 0.7 μM, respectively. In MERS-CoV-infected cells, the inhibitors showed antiviral activity with EC50values ranging from 0.6 to 1.4 μM, by downregulating the viral protein production in cells as well as reducing secretion of infectious viral particles into culture supernatants. They also suppressed other α- and β-CoVs from human and feline origin. These compounds exhibited good selectivity index (over 70 against MERS-CoV) and could lead to the development of broad-spectrum antiviral drugs against emerging CoVs and picornaviruses.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Vathan
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Jiun-Jie
authors.initials: JJ
authors.lastname: Shie
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Keun Bon
authors.initials: KB
authors.lastname: Ku
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Chonsaeng
authors.initials: C
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Yun Young
authors.initials: YY
authors.lastname: Go
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Kai-Fa
authors.initials: KF
authors.lastname: Huang
authors.affiliation: Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. Electronic address: mkim@krict.re.kr.
authors.forename: Meehyein
authors.initials: M
authors.lastname: Kim
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan. Electronic address: phliang@gate.sinica.edu.tw.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Liang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002415:Cats; D017934:Coronavirus / Q000187:drug effects; D018352:Coronavirus Infections / Q000821:virology; D055808:Drug Discovery; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000187:drug effects*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects; D014764:Viral Proteins
chemical_list: D000998:Antiviral Agents; D057786:Peptidomimetics; D011480:Protease Inhibitors; D014764:Viral Proteins
keywords: 3C-like protease; Coronavirus; MERS-CoV; Peptidomimetic inhibitor; Picornavirus; SARS-CoV