Aib-based peptide backbone as scaffolds for helical peptide mimics.
Helical peptides that can intervene and disrupt therapeutically important protein-protein interactions are attractive drug targets. In order to develop a general strategy for developing such helical peptide mimics, we have studied the effect of incorporating alpha-amino isobutyric acid (Aib), an amino acid with strong preference for helical backbone, as the sole helix promoter in designed peptides. Specifically, we focus on the hdm2-p53 interaction, which is central to development of many types of cancer. The peptide corresponding to the hdm2 interacting part of p53, helical in bound state but devoid of structure in solution, served as the starting point for peptide design that involved replacement of noninteracting residues by Aib. Incorporation of Aib, while preserving the interacting residues, led to significant increase in helical structure, particularly at the C-terminal region as judged by nuclear magnetic resonance and circular dichroism. The interaction with hdm2 was also found to be enhanced. Most interestingly, trypsin cleavage was found to be retarded by several orders of magnitude. We conclude that incorporation of Aib is a feasible strategy to create peptide helical mimics with enhanced receptor binding and lower protease cleavage rate.
Banerjee
Raja
R
Department of Biophysics, Bose Institute, Calcutta, India.
Basu
Gautam
G
Chène
Patrick
P
Roy
Siddhartha
S
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000621:Aminoisobutyric Acids / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D014357:Trypsin / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
D000596:Amino Acids; D000621:Aminoisobutyric Acids; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D014357:Trypsin