Proven in vitro evolution of protease cathepsin E-inhibitors and -activators at pH 4.5 using a paired peptide method

Koichiro Kitamura, Masayuki Komatsu, Madhu Biyani, Masae Futakami, Tomoyo Kawakubo, Kenji Yamamoto, Koichi Nishigaki

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Improving a particular function of molecules is often more difficult than identifying such molecules ab initio. Here, a method to acquire higher affinity and/or more functional peptides was developed as a progressive library selection method. The primary library selection products were utilized to build a secondary library composed of blocks of 4 amino acids, of which selection led to peptides with increased activity. These peptides were further converted to randomly generate paired peptides. Cathepsin E-inhibitors thus obtained exhibited the highest activities and affinities (pM order). This was also the case with cathepsin E-activating peptides, proving the methodological effectiveness. The primary, secondary, and tertiary library selections can be regarded as module-finding, module-shuffling, and module-pairing, respectively, which resembles the progression of the natural evolution of proteins. The mode of peptide binding to their target proteins is discussed in analogy to antibodies and epitopes of an antigen.

Original languageEnglish
Pages (from-to)711-719
Number of pages9
JournalJournal of Peptide Science
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2012

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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