Metabolic stability of peptidomimetics: N-methyl and aza heptapeptide analogs of a PKB/Akt inhibitor

Yftah Tal-Gan, Noam S. Freeman, Shoshana Klein, Alexander Levitzki, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Linear peptides suffer from poor pharmacokinetic and pharmacodynamic properties. Peptidomimetics are designed to overcome these pharmacological drawbacks while maintaining the biological effects of the parent peptides. Aza-peptides, in which an alpha carbon is replaced with nitrogen, are promising peptidomimetic analogs; however, little is known about the stability of these analogs toward enzymatic degradation. We performed systematic aza and N-methyl scans of a PKB/Akt inhibitor, PTR6154. We evaluated the stability of the aza-scan and N-methyl scan libraries toward enzymatic degradation by trypsin/chymotrypsin. Our results indicate that the modification site is important for metabolic stability and that aza-peptides have a more global effect than N-methylation, affecting cleavage sites distant from the modification site.

Original languageEnglish
Pages (from-to)887-892
Number of pages6
JournalChemical Biology and Drug Design
Volume78
Issue number5
DOIs
StatePublished - Nov 2011

Keywords

  • Aza-peptide
  • Chymotrypsin
  • N-methylation
  • Peptidomimetics
  • PKB/Akt
  • Trypsin

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