Metabolic Stability of Peptidomimetics: N‐Methyl and Aza Heptapeptide Analogs of a PKB/Akt Inhibitor

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.

Development of a Dominant Negative Competence‐Stimulating Peptide (dnCSP) that Attenuates Streptococcus pneumoniae Infectivity in a Mouse Model of Acute Pneumonia

“…Because our SAR study did not yield new dnCSPs with higher potencies or pan‐group reactivity, we evaluated the therapeutic potential of the previously reported lead ComD1 and ComD2 dnCSPs, CSP1‐E1A and CSP2‐E1Ad10, respectively. First, we assessed the metabolic stability of CSP1‐E1A and CSP2‐E1Ad10 by using an in vitro trypsin/chymotrypsin stability assay . The stability of the two dnCSPs was compared against CSP1 and CSP2.…”

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A3‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

“…Azapeptides are peptide mimics that contain one or multiple semicarbazides, in which nitrogen replaces an amino acid residue α‐carbon . Aza‐residues can favor β‐turn geometry and enhance peptide metabolic stability . Linear azapeptides have been established as drugs; however, their macrocycle counterparts have only begun to be explored .…”

Methods to Enhance the Metabolic Stability of Peptide-Based PET Radiopharmaceuticals

“…With the overall conformational change that can occur with N-methylated peptides, and the change in H-bonding capacity and steric features, N-methylation often leads to a decreased affinity of the peptide for the active site of proteases and therefore increased metabolic stability. It has also been found that N-methylation of an amide bond adjacent to the cleavage site can confer a greater resistance against enzymatic degradation than N-methylation of the amide bond at the cleavage site itself [89]. This behavior may result from N-methylation making the cis conformation readily accessible and then becoming the preferred conformation of the peptide in vivo.…”