title: Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors.
abstract: Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612-7231, USA.
authors.forename: Isaac T
authors.initials: IT
authors.lastname: Schiefer
authors.forename: Subhasish
authors.initials: S
authors.lastname: Tapadar
authors.forename: Vladislav
authors.initials: V
authors.lastname: Litosh
authors.forename: Marton
authors.initials: M
authors.lastname: Siklos
authors.forename: Rob
authors.initials: R
authors.lastname: Scism
authors.forename: Gihani T
authors.initials: GT
authors.lastname: Wijewickrama
authors.forename: Esala P
authors.initials: EP
authors.lastname: Chandrasena
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sinha
authors.forename: Ehsan
authors.initials: E
authors.lastname: Tavassoli
authors.forename: Michael
authors.initials: M
authors.lastname: Brunsteiner
authors.forename: Mauro
authors.initials: M
authors.lastname: Fa'
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Pavel
authors.initials: P
authors.lastname: Petukhov
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D057930:Click Chemistry; D003198:Computer Simulation; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D062105:Molecular Docking Simulation; D010206:Papain / Q000037:antagonists & inhibitors; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004852:Epoxy Compounds; D057786:Peptidomimetics; D002154:Calpain; D010206:Papain; D007930:Leucine; C024974:E 64