title: Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis.
abstract: Opening of the mitochondrial permeability transition pore (MPTP) causes mitochondrial dysfunction and necrosis in acute pancreatitis (AP), a condition without specific drug treatment. Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomerase that regulates the MPTP and is a drug target for AP. We have synthesized urea-based small molecule inhibitors of cyclophilins and tested them against CypD using binding and isomerase activity assays. Thermodynamic profiles of the CypD/inhibitor interactions were determined by isothermal titration calorimetry. Seven new high-resolution crystal structures of CypD-inhibitor complexes were obtained to guide compound optimization. Compounds 4, 13, 14, and 19 were tested in freshly isolated murine pancreatic acinar cells (PACs) to determine inhibition of toxin-induced loss of mitochondrial membrane potential (ΔΨm) and necrotic cell death pathway activation. Compound 19 was found to have a Kd of 410 nM and a favorable thermodynamic profile, and it showed significant protection of ΔΨm and reduced necrosis of murine as well as human PACs. Compound 19 holds significant promise for future lead optimization.
authors.affiliation: Department of Chemistry, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Shore
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Awais
authors.affiliation: Department of Chemistry, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Kershaw
authors.affiliation: Institute of Integrative Biology, Biosciences Building, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Gibson
authors.affiliation: Institute of Integrative Biology, Biosciences Building, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Sravan
authors.initials: S
authors.lastname: Pandalaneni
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: Diane
authors.initials: D
authors.lastname: Latawiec
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Javed
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
authors.affiliation: Department of Chemistry, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.affiliation: Department of Chemistry, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: Institute of Integrative Biology, Biosciences Building, University of Liverpool , Crown Street, Liverpool L69 7ZD, United Kingdom.
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Royal Liverpool University Hospital , Daulby Street, Liverpool L7 8XP, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Sutton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009336:Necrosis; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy*; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C000622958:1-(4-aminobenzyl)-3-(4-(methylthio)-1-(2-(2-(methylthio)phenyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)urea; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D011759:Pyrrolidines; D054852:Small Molecule Libraries; D014508:Urea; D021983:Cyclophilins