| Full text | |
| Author(s): Show less - |
Oliveira, Jocelia P. C.
[1]
;
Freitas, Renato F.
[2]
;
de Melo, Leandro Silva
[1]
;
Barros, Thalita G.
[3]
;
Santos, Jorge A. N.
[4]
;
Juliano, Maria A.
[5]
;
Pinheiro, Sergio
[6]
;
Blaber, Michael
[7]
;
Juliano, Luiz
[5]
;
Muri, Estela M. F.
[3]
;
Puzer, Luciano
[1]
Total Authors: 11
|
| Affiliation: | [1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil
[2] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 - USA
[3] Univ Fed Fluminense, Fac Farm, BR-24220008 Niteroi, RJ - Brazil
[4] Inst Fed Educ Ciencia & Tecnol Sul Minas Gerais, BR-37576000 Inconfidentes, MG - Brazil
[5] Univ Fed Sao Paulo, Dept Biofis, BR-04107001 Sao Paulo - Brazil
[6] Univ Fed Fluminense, Inst Quim, BR-24220008 Niteroi, RJ - Brazil
[7] Florida State Univ, Dept Biomed Sci, Tallahassee, FL 32306 - USA
Total Affiliations: 7
|
| Document type: | Journal article |
| Source: | ACS Medicinal Chemistry Letters; v. 5, n. 2, p. 128-132, FEB 2014. |
| Web of Science Citations: | 20 |
| 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 mu M) 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. (AU) | |
| FAPESP's process: | 12/50191-4 - Synthesis, kinetic studies and applications of substrates and inhibitors for proteolytic enzymes |
| Grantee: | Maria Aparecida Juliano |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 11/51297-8 - Development of inhibitors for human tissue kallikreins 5 and 7 (KLK5 and KLK7) |
| Grantee: | Luciano Puzer |
| Support Opportunities: | Regular Research Grants |