title: Inhibition of enterovirus 71 replication by an α-hydroxy-nitrile derivative NK-1.9k.
abstract: Enterovirus 71 (EV71) is one of the major etiological agents of human hand-foot-and-mouth disease (HFMD) worldwide. EV71 infection in young children and people with immunodeficiency causes severe symptoms with a high fatality rates. However, there is still no approved drugs to treat such infections. Based on our previous report of a peptide-aldehyde anti-EV71 protease, we present here a highly specific α-hydroxy-nitrile derivative NK-1.9k, which inhibited the proliferation of multiple EV71 strains and coxsackievirus A16 (CVA16) in various cells with EC50of 37.0 nM with low cytotoxicity (CC50> 200 μM). The hydroxy-nitrile covalent warhead conferred NK-1.9k high potency and selectivity to interact with the cysteine residue of the active site of the viral protease. We also documented the resistance to NK-1.9k with a N69S mutation in EV71 3Cpro. The combination of NK-1.9k and EV71 polymerase or entry inhibitors produced strong synergistic antiviral effects. Collectively, our findings suggest our compounds can potentially be developed as drugs for the treatment of HFMD.
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China; National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: The High School Affiliated to Renmin University of China, Beijing, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Ma
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
authors.forename: Quandeng
authors.initials: Q
authors.lastname: Nie
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China. Electronic address: sunyn@moon.ibp.ac.cn.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Pharmacy & State Key Laboratory of Medicinal Chemical Biology & Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China. Electronic address: shanglq@nankai.edu.cn.
authors.forename: Luqing
authors.initials: L
authors.lastname: Shang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004261:DNA Replication / Q000187:drug effects; D055808:Drug Discovery; D004770:Enterovirus / Q000187:drug effects; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006232:Hand, Foot and Mouth Disease / Q000188:drug therapy / Q000821:virology; D009154:Mutation; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C000625579:NK-1.9k; D009570:Nitriles; D057786:Peptidomimetics; D011728:Pyridones; D010649:Phenylalanine
keywords: EV71; Inhibitor; Protease; α-hydroxy-nitrile