2. Academic Validation
  3. Isomannide-based peptidomimetics as inhibitors for human tissue kallikreins 5 and 7

Isomannide-based peptidomimetics as inhibitors for human tissue kallikreins 5 and 7

  • ACS Med Chem Lett. 2013 Dec 6;5(2):128-32. doi: 10.1021/ml4003698.
Jocelia P C Oliveira 1,  Renato F Freitas 2,  Leandro Silva de Melo 1,  Thalita G Barros 3,  Jorge A N Santos 4,  Maria A Juliano 5,  Sérgio Pinheiro 6,  Michael Blaber 7,  Luiz Juliano 5,  Estela M F Muri 3,  Luciano Puzer 1
Affiliations

Affiliations

  • 1 Centro de Ciências Naturais e Humanas, Universidade Federal do ABC , Rua Santa Adélia 166, Bairro Bangu, Santo André SP, 09210-170, Brazil.
  • 2 Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
  • 3 Faculdade de Farmácia, Universidade Federal Fluminense , R. Miguel de Frias, 9 - Icaraí, Niterói, RJ, 24220-008, Brazil.
  • 4 Instituto Federal de Educação, Ciência e Tecnologia do Sul de Minas Gerais, Inconfidentes , MG, 37576-000, Brazil.
  • 5 Departamento de Biofísica, Universidade Federal de São Paulo , Rua Três de Maio 100, São Paulo, SP, 04107-001, Brasil.
  • 6 Instituto de Química, Universidade Federal Fluminense , R. Miguel de Frias, 9 - Icaraí, Niterói, RJ 24220-008, Brazil.
  • 7 Department of Biomedical Sciences, Florida State University , 600 West College Avenue, Tallahassee, Florida 32306, United States.
PMID: 24900785 DOI: 10.1021/ml4003698
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.

Keywords

Serine protease; inhibitor; kallikrein; molecular dynamics; peptidomimetics.

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