Development of systemic in vitro evolution and its application to generation of peptide-aptamer-based inhibitors of cathepsin E

Journal of Molecular Biology
Koichiro KitamuraKoichi Nishigaki

Abstract

Proteases are involved in various biological functions. Thus, inhibition of their activities is scientifically interesting and medically important. However, there is no systematic method established to date to generate endopeptidase inhibitory peptides. Here, we report a general system to identify endopeptidase inhibitory peptides based on the use of in vitro evolution. Using this system, we generated peptides that inhibit cathepsin E (CE) specifically at a submicromolar IC(50). This system generates protease inhibitor peptides utilizing techniques of cDNA display, selection-by-function, Y-ligation-based block shuffling, and others. We further demonstrated the importance and effectiveness of a secondary library for obtaining small-sized and active peptides. CE inhibitory peptides generated by this method were characterized by a small size (8 to 12 aa) and quite different sequences, suggesting that they bind to different sites on CE. Typical CE inhibitory peptide aptamers obtained here (P(i)101; SCGG IIII SCIA) have half an inhibition activity (K(i); 5 nM) of pepstatin A (potent CE inhibitor) without inhibiting cathepsin D (structurally similar to CE). The general applicability of this system suggests that it may be useful to id...Continue Reading

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Citations

Jun 23, 2012·Proceedings of the National Academy of Sciences of the United States of America·Shingo UenoTakafumi Sakai
Feb 1, 2013·International Journal of Peptides·Masayuki KomatsuKoichi Nishigaki
Apr 30, 2011·International Journal of Peptides·Madhu BiyaniKoichi Nishigaki
Nov 27, 2009·Computational Biology and Chemistry·Takuyo AitaYuzuru Husimi
Feb 24, 2011·Journal of Cellular Physiology·Paola MatarreseAnna Teresa Palamara
Oct 31, 2012·Journal of Peptide Science : an Official Publication of the European Peptide Society·Koichiro KitamuraKoichi Nishigaki
Aug 2, 2014·Chemical Biology & Drug Design·Sunita Ghimire GautamKoichi Nishigaki
Jul 15, 2015·Journal of Peptide Science : an Official Publication of the European Peptide Society·Yumiko HayakawaMakoto Hasegawa
Apr 17, 2012·Biochemical and Biophysical Research Communications·Naoto NemotoTakafumi Sakai
Mar 17, 2017·Frontiers in Immunology·Jörg MengwasserOlaf Penack
Jan 1, 2010·BioTechniques·Md SalimullahPiero Carninci
Jul 23, 2018·Analytical Biochemistry·Kirti SharmaManish Biyani
Jul 6, 2010·Biochimica Et Biophysica Acta·Wael R Abd-Elgaliel, Ching-Hsuan Tung

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