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Metabolic Stability of Peptidomimetics: N ‐Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor
Author(s) -
TalGan Yftah,
Freeman Noam S.,
Klein Shoshana,
Levitzki Alexander,
Gilon Chaim
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01207.x
Subject(s) - peptidomimetic , metabolic stability , chemistry , stereochemistry , enzyme , trypsin , biochemistry , peptide , in vitro
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.