title: X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design.
abstract: Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC50=0.59±0.06 μM) and compound 7 (IC50=1.3±0.1 μM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10 Å to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture.
authors.affiliation: Departments of Biochemistry and Biological Sciences, Purdue University, West Lafayette, IN, USA; Centers for Cancer Research & Drug Discovery, Purdue University, West Lafayette, IN, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: St John
authors.affiliation: Departments of Biochemistry and Biological Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Therkelsen
authors.affiliation: Centers for Cancer Research & Drug Discovery, Purdue University, West Lafayette, IN, USA.
authors.forename: Prasanth R
authors.initials: PR
authors.lastname: Nyalapatla
authors.affiliation: Centers for Cancer Research & Drug Discovery, Purdue University, West Lafayette, IN, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Osswald
authors.affiliation: Centers for Cancer Research & Drug Discovery, Purdue University, West Lafayette, IN, USA; Department of Chemistry, Purdue University, West Lafayette, IN, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Departments of Biochemistry and Biological Sciences, Purdue University, West Lafayette, IN, USA; Centers for Cancer Research & Drug Discovery, Purdue University, West Lafayette, IN, USA; Department of Chemistry, Purdue University, West Lafayette, IN, USA. Electronic address: amesecar@purdue.edu.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D020134:Catalytic Domain; D000086782:Coronavirus 3C Proteases; D016765:Coronavirus, Feline / Q000201:enzymology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004926:Escherichia coli; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D057786:Peptidomimetics; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases
keywords: 3CLpro; Coronavirus; Feline infectious peritonitis; Peptidomimetics; Structure-based drug design