title: Design and synthesis of irreversible inhibitors of foot-and-mouth disease virus 3C protease.
abstract: Foot-and-mouth disease virus (FMDV) causes a highly infectious and economically devastating disease of livestock. The FMDV genome is translated as a single polypeptide precursor that is cleaved into functional proteins predominantly by the highly conserved viral 3C protease, making this enzyme an attractive target for antiviral drugs. A peptide corresponding to an optimal substrate has been modified at the C-terminus, by the addition of a warhead, to produce irreversible inhibitors that react as Michael acceptors with the enzyme active site. Further investigation highlighted key structural determinants for inhibition, with a positively charged P2 being particularly important for potency.
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Núria R
authors.initials: NR
authors.lastname: Roqué Rosell
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Ladan
authors.initials: L
authors.lastname: Mokhlesi
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Milton
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Sweeney
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Zunszain
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Curry
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom; Egerton Court, Liverpool John Moores University, Liverpool L1 2UA, United Kingdom. Electronic address: r.leatherbarrow@imperial.ac.uk.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D029544:Foot-and-Mouth Disease Virus / Q000187:drug effects* / Q000201:enzymology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
keywords: 3C protease; Cysteine protease; Foot-and-mouth disease virus; Irreversible inhibitor; Warhead