Selection of effective HTRA3 activators using combinatorial chemistry

Magdalena Wysocka , Kamila Sychowska , Natalia Gruba , Łukasz Winiarski , Marcin Skoreński , Mateusz Psurski , Joanna Makowska , Artur Giełdoń , Tomasz Wenta , Mirosław Jarząb , Przemysław Glaza , Joanna Zdancewicz , Marcin Sieńczyk , Adam Lesner


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.
Author Magdalena Wysocka (FCh / DBCh / LMCh)
Magdalena Wysocka,,
- Laboratory of Medical Chemistry
, Kamila Sychowska (FCh / DMB / LBA)
Kamila Sychowska,,
- Laboratory of Biochemical Analytics
, Natalia Gruba (FCh / DMB / LBA)
Natalia Gruba,,
- Laboratory of Biochemical Analytics
, Łukasz Winiarski
Łukasz Winiarski,,
, Marcin Skoreński
Marcin Skoreński,,
, Mateusz Psurski
Mateusz Psurski,,
, Joanna Makowska (FCh / DGICh / PBChN)
Joanna Makowska,,
- Pracownia Biologicznej Chemii Nieorganicznej
, Artur Giełdoń (FCh / DTCh / LSP)
Artur Giełdoń,,
- Laboratory of Simulation of Polymers
, Tomasz Wenta (FB / DB)
Tomasz Wenta,,
- Department of Biochemistry
, Mirosław Jarząb (FB / DB)
Mirosław Jarząb,,
- Department of Biochemistry
et al.`
Journal seriesACS Combinatorial Science, ISSN 2156-8952, (A 30 pkt)
Issue year2017
Publication size in sheets0.5
Keywords in EnglishHTRA3 protease, combinatorial chemistry, molecular modeling, peptidomimetic library
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 30.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Citations = 0; WoS Impact Factor: 2017 = 3.5 (2) - 2017=2.923 (5)
Citation count*
Share Share

Get link to the record

* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.