TY - JOUR
T1 - Metabolic stability of peptidomimetics
T2 - N-methyl and aza heptapeptide analogs of a PKB/Akt inhibitor
AU - Tal-Gan, Yftah
AU - Freeman, Noam S.
AU - Klein, Shoshana
AU - Levitzki, Alexander
AU - Gilon, Chaim
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
KW - Aza-peptide
KW - Chymotrypsin
KW - N-methylation
KW - Peptidomimetics
KW - PKB/Akt
KW - Trypsin
UR - http://www.scopus.com/inward/record.url?scp=80054092007&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2011.01207.x
DO - 10.1111/j.1747-0285.2011.01207.x
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C2 - 21824328
AN - SCOPUS:80054092007
SN - 1747-0277
VL - 78
SP - 887
EP - 892
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 5
ER -