Startseite Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6

  • Beatrice Severino EMAIL logo , Ferdinando Fiorino , Angela Corvino , Giuseppe Caliendo , Vincenzo Santagada , Diego Magno Assis , Juliana R. Oliveira , Luiz Juliano , Serena Manganelli , Emilio Benfenati , Francesco Frecentese , Elisa Perissutti und Maria Aparecida Juliano
Veröffentlicht/Copyright: 31. Juli 2014

Abstract

A series of protease activated receptor 2 activating peptide (PAR2-AP) derivatives (1–15) were designed and synthesized. The obtained compounds were tested on a panel of human kallikreins (hKLK1, hKLK2, hKLK5, hKLK6, and hKLK7) and were found completely inactive toward hKLK1, hKLK2, and hKLK7. Aiming to investigate the mode of interaction between the most interesting compounds and the selected hKLKs, docking studies were performed. The described compounds distinguish the different human tissue kallikreins with compounds 1 and 5 as the best hKLK5 and hKLK6 inhibitors, respectively.


Corresponding author: Beatrice Severino, Dipartimento di Farmacia, Università degli Studi di Napoli ‘Federico II’, Via D. Montesano, 49, I-80131 Napoli, Italy, e-mail:

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP – project-12/50191-4R), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – projects 471340/2011-1 and 470388/2010-2).

References

Angelo, P.F., Lima, A.R., Alves, F.M., Blaber, S.I., Scarisbrick I.A., Blaber, M., Juliano, L., and Juliano, M.A. (2006). Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects. J. Biol. Chem. 281, 3116–3126.10.1074/jbc.M510096200Suche in Google Scholar

Bernett, M.J., Blaber, S.I., Scarisbrick, I.A., Dhanarajan, P., Thompson, S.M., and Blaber, M. (2002). Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem. 277, 24562–24570.10.1074/jbc.M202392200Suche in Google Scholar

Brattsand, M. and Egelrud, T. (1999). Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J. Biol. Chem. 274, 30033–30040.10.1074/jbc.274.42.30033Suche in Google Scholar

Briot, A., Deraison, C., Lacroix, M., Bonnart, C., Robin, A., Besson, C., Dubus, P., and Hovnanian, A. (2009). Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 206, 1135–1147.10.1084/jem.20082242Suche in Google Scholar

Caliendo, G., Santagada, V., Perissutti, E., Severino, B., Fiorino, F., Frecentese, F., and Juliano, L. (2012). Kallikrein protease activated receptor (PAR) axis: an attractive target for drug development. J. Med. Chem. 55, 6669–6686.10.1021/jm300407tSuche in Google Scholar

Debela, M., Magdolen, V., Schechter, N., Valachova, M., Lottspeich, F., Craik, C.S., Choe, Y., Bode, W., and Goettig, P. (2006). Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. J. Biol. Chem. 281, 25678–25688.10.1074/jbc.M602372200Suche in Google Scholar

Debela, M., Beaufort, N., Magdolen, V., Schechter, N.M., Craik, C.S., Schmitt, M., Bode, W., and Goettig, P. (2008). Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7. Biol. Chem. 389, 623–632.10.1515/BC.2008.075Suche in Google Scholar

Diamandis, E.P., Yousef, G.M., Petraki, C., and Soosaipillai, A.R. (2000). Human kallikrein 6 as a biomarker of Alzheimer’s disease. Clin. Biochem. 33, 663–667.10.1016/S0009-9120(00)00185-5Suche in Google Scholar

Goldberg D.E. (1989). Genetic Algorithms in Search, Optimization, and Machine Learning (Reading, MA: Addison-Wesley).Suche in Google Scholar

Hovnanian, A. (2012). Netherton syndrome: new advances in the clinic, disease mechanism and treatment. Exp. Rev. Dermatol. 7, 81–92.10.1586/edm.11.85Suche in Google Scholar

Jameson, G.W., Roberts, D.V., Adams, R.W., Kyle, W.S.A., and Elmore, D.T. (1973). Determination of the operational molarity of solutions of bovine α-chymotrypsin, trypsin, thrombin and factor Xa by spectrofluorimetric titration. Biochem. J. 131, 107–117.10.1042/bj1310107Suche in Google Scholar PubMed PubMed Central

Leach, A.R. and Gillet, V.J. (2007). An Introduction to Chemoinformatics (Dordrecht, the Netherlands: Springer).10.1007/978-1-4020-6291-9Suche in Google Scholar

Liang, G., Chen, X., Aldous, S., Pu, S.F., Mehdi, S., Powers, E., Xia, T., and Wang, R. (2012a). Human kallikrein 6 inhibitors with a para-amidobenzylanmine P1 group identified through virtual screening. Bioorg. Med. Chem. Lett. 22, 2450–2455.10.1016/j.bmcl.2012.02.014Suche in Google Scholar

Liang, G., Chen, X., Aldous, S., Pu, S.F., Mehdi, S., Powers, E., Giovanni, A., Kongsamut, S., Xia, T., Zhang, Y., et al. (2012b). Virtual screening and X-ray crystallography for human kallikrein 6 inhibitors with an amidinothiophene P1 group. ACS Med. Chem. Lett. 3, 159–164.10.1021/ml200291eSuche in Google Scholar

Michael, I.P., Sotiropoulou, G., Pampalakis, G., Magklara, A., Ghosh, M., Wasney, G., and Diamandis, E.P. (2005). Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression. J. Biol. Chem. 280, 14628–14635.10.1074/jbc.M408132200Suche in Google Scholar

Michael, I.P., Pampalakis, G., Mikolajczyk, S.D., Malm, J., Sotiropoulou, G., and Diamandis, E.P. (2006). Human tissue kallikrein 5 is a member of a proteolytic cascade pathway involved in seminal clot liquefaction and potentially in prostate cancer progression. J. Biol. Chem. 281, 12743–12750.10.1074/jbc.M600326200Suche in Google Scholar

Ogawa, K., Yamada, T., Tsujioka, Y., Taguchi, J., Takahashi, M., Tsuboi, Y., Fujino, Y., Nakajima, M., Yamamoto, T., Akatsu, H., et al. (2000). Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer’s disease and Parkinson’s disease. Psychiatry Clin. Neurosci. 54, 419–426.10.1046/j.1440-1819.2000.00731.xSuche in Google Scholar

Santagada, V., Caliendo, G., Severino, B., Perissutti, E., Fiorino, F., Cicala, C., De Filippis, V., and Cirino, G. (2002). Minimal structural requirements for agonist activity of PAR-2 activating peptides. Bioorg. Med. Chem. Lett. 12, 21–24.10.1016/S0960-894X(01)00636-9Suche in Google Scholar

Scarisbrick, I.A., Linbo, R., Vandell, A.G., Keegan, M., Blaber, S.I., Blaber, M., Sneve, D., Lucchinetti, C.F., Rodriguez, M., and Diamandis, E.P. (2008). Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration. Biol. Chem. 389, 739–745.10.1515/BC.2008.085Suche in Google Scholar PubMed PubMed Central

Shaw, J.L.V. and Diamandis, E.P. (2007). Distribution of 15 human kallikreins in tissues and biological fluids. Clin. Chem. 53, 1423–1432.10.1373/clinchem.2007.088104Suche in Google Scholar PubMed

Teixeira, T.S.P., Freitas, R.F., Abrahao, Jr., A., Devienne, K.F., de Souza, L.R., Blaber, S.I., Blaber, M., Kondo, M.J., Juliano, M.A., Juliano, L., et al. (2011). Biological evaluation and docking studies of natural isocoumarins as inhibitors for human kallikrein 5 and 7. Bioorg. Med. Chem. Lett. 21, 6112–6115.10.1016/j.bmcl.2011.08.044Suche in Google Scholar PubMed

Vandell, A.G., Larson, N., Laxmikanthan, G., Panos, M., Blaber, S.I., Blaber, M., and Scarisbrick, I.A. (2008). Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J. Neurochem. 107, 855–870.10.1111/j.1471-4159.2008.05658.xSuche in Google Scholar PubMed PubMed Central

Yousef, G.M. and Diamandis, E.P. (2001). The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr. Rev. 22, 184–204.Suche in Google Scholar

Yousef, G.M., Chang, A., Scorilas, A., and Diamandis, E.P. (2000). Genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. Biochem. Biophys. Res. Commun. 276, 125–133.10.1006/bbrc.2000.3448Suche in Google Scholar PubMed

Received: 2014-4-22
Accepted: 2014-7-25
Published Online: 2014-7-31
Published in Print: 2015-1-1

©2014 by De Gruyter

Heruntergeladen am 29.11.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2014-0190/html
Button zum nach oben scrollen