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

Title: Isomannide-based peptidomimetics as inhibitors for human tissue kallikreins 5 and 7.
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Name(s): Oliveira, Jocelia P C, author
Freitas, Renato F, author
Melo, Leandro Silva de, author
Barros, Thalita G, author
Santos, Jorge A N, author
Juliano, Maria A, author
Pinheiro, Sérgio, author
Blaber, Michael, author
Juliano, Luiz, author
Muri, Estela M F, author
Puzer, Luciano, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2013-12-06
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_24900785 (IID), 10.1021/ml4003698 (DOI), PMC4027626 (PMCID), 24900785 (RID), 24900785 (EID)
Keywords: Serine protease, Inhibitor, Kallikrein, Molecular dynamics, Peptidomimetics
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027626.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_24900785
Owner Institution: FSU
Is Part Of: ACS medicinal chemistry letters.
1948-5875
Issue: iss. 2, vol. 5

Choose the citation style.
Oliveira, J. P. C., Freitas, R. F., Melo, L. S. de, Barros, T. G., Santos, J. A. N., Juliano, M. A., … Puzer, L. (2013). Isomannide-based peptidomimetics as inhibitors for human tissue kallikreins 5 and 7. Acs Medicinal Chemistry Letters. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_24900785