Selection of Effective HTRA3 Activators Using Combinatorial Chemistry

Autor:	Kamila Sychowska, Łukasz Winiarski, Mirosław Jarząb, Marcin Skoreński, Mateusz Psurski, Przemyslaw Glaza, Marcin Sieńczyk, Adam Lesner, Artur Giełdoń, Barbara Lipinska, Tomasz Wenta, Natalia Gruba, Magdalena Wysocka, Joanna Makowska, Joanna Zdancewicz
Rok vydání:	2017
Předmět:	Models Molecular 0301 basic medicine Molecular model Protein Conformation Peptidomimetic Proteolysis medicine.medical_treatment PDZ domain Enzyme Activators PDZ Domains Antineoplastic Agents Substrate Specificity 03 medical and health sciences 0302 clinical medicine Peptide Library Cell Line Tumor medicine Combinatorial Chemistry Techniques Humans Amino Acid Sequence Selection (genetic algorithm) chemistry.chemical_classification Protease medicine.diagnostic_test Serine Endopeptidases Substrate (chemistry) General Chemistry General Medicine Combinatorial chemistry 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis Peptidomimetics Oligopeptides Protein Binding
Zdroj:	ACS Combinatorial Science. 19:565-573
ISSN:	2156-8944 2156-8952
DOI:	10.1021/acscombsci.7b00051
Popis:	Herein, we report selection, synthesis, and enzymatic evaluation of a peptidomimetic library able to increase proteolytic activity of HtrA3 (high temperature requirement A) protease. Iterative deconvolution in solution of synthesized modified pentapeptides yielded two potent HtrA3 activators acting in the micromolar range (HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Asn-OH and HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Glu-OH). Both compounds increased proteolysis of an artificial HtrA3 substrate over 40-fold in a selective manner. On the basis of molecular modeling, the selected compounds bind strongly to the PDZ domain.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0a69ce8edcefefa00178d4062557551b https://doi.org/10.1021/acscombsci.7b00051 Zobrazit plný text záznamu