title: Isomannide-based peptidomimetics as inhibitors for human tissue kallikreins 5 and 7.
abstract: Human kallikrein 5 (KLK5) and 7 (KLK7) are potential targets for the treatment of skin inflammation and cancer. Previously, we identified isomannide derivatives as potent and competitive KLK7 inhibitors. The introduction of N-protected amino acids into the isomannide-based scaffold was studied. Some KLK5 inhibitors with submicromolar affinity (K i values of 0.3-0.7 μM) were identified, and they were 6- to 13-fold more potent than our previous hits. Enzyme kinetics studies and the determination of the mechanism of inhibition confirmed that the new isomannide-based derivatives are competitive inhibitors of both KLK5 and KLK7. Molecular docking and MD simulations of selected inhibitors into the KLK5 binding site provide insight into the molecular mechanism by which these compounds interact with the enzyme. The promising results obtained in this study open new prospects on the design and synthesis of highly specific KLK5 and KLK7 inhibitors.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC , Rua Santa Adélia 166, Bairro Bangu, Santo André SP, 09210-170, Brazil.
authors.forename: Jocelia P C
authors.initials: JP
authors.lastname: Oliveira
authors.affiliation: Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Renato F
authors.initials: RF
authors.lastname: Freitas
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC , Rua Santa Adélia 166, Bairro Bangu, Santo André SP, 09210-170, Brazil.
authors.forename: Leandro Silva de
authors.initials: LS
authors.lastname: Melo
authors.affiliation: Faculdade de Farmácia, Universidade Federal Fluminense , R. Miguel de Frias, 9 - Icaraí, Niterói, RJ, 24220-008, Brazil.
authors.forename: Thalita G
authors.initials: TG
authors.lastname: Barros
authors.affiliation: Instituto Federal de Educação, Ciência e Tecnologia do Sul de Minas Gerais, Inconfidentes , MG, 37576-000, Brazil.
authors.forename: Jorge A N
authors.initials: JA
authors.lastname: Santos
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo , Rua Três de Maio 100, São Paulo, SP, 04107-001, Brasil.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Juliano
authors.affiliation: Instituto de Química, Universidade Federal Fluminense , R. Miguel de Frias, 9 - Icaraí, Niterói, RJ 24220-008, Brazil.
authors.forename: Sérgio
authors.initials: S
authors.lastname: Pinheiro
authors.affiliation: Department of Biomedical Sciences, Florida State University , 600 West College Avenue, Tallahassee, Florida 32306, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo , Rua Três de Maio 100, São Paulo, SP, 04107-001, Brasil.
authors.forename: Luiz
authors.initials: L
authors.lastname: Juliano
authors.affiliation: Faculdade de Farmácia, Universidade Federal Fluminense , R. Miguel de Frias, 9 - Icaraí, Niterói, RJ, 24220-008, Brazil.
authors.forename: Estela M F
authors.initials: EM
authors.lastname: Muri
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC , Rua Santa Adélia 166, Bairro Bangu, Santo André SP, 09210-170, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: Puzer
keywords: Serine protease; inhibitor; kallikrein; molecular dynamics; peptidomimetics