Macrocyclic a-helical peptides

MDM2/MDMX antagonist stapled peptide ATSP-7041 vide infra) provides an in-depth and rigorous in vitro and in vivo proof-of-concept for drug development of this promising class of macrocyclic a-helical peptide therapeutics. 

Understanding the Cell Penetration Properties of Macrocyclic a-Helical Peptides... 

Unquestionably, there is significant interest in understanding the cell penetration properties of macrocyclic a-helical peptides. Such work is now the focus of ongoing basic research that will leverage sophisticated biochemical, cellular and biophysical methods to address the complexity of molecular mechanisms involved in cell penetration by stapled peptides. For example, highly potent macrocyclic a-helical peptides such as the stapled peptide ATSP-7041 provide opportunistic tool molecules to interrogate cell penetration relative to cellular uptake mechanisms and peptide biophysical properties, including the establishment of benchmarks and standardized procedures. 

Figure 9.2 Examples of macrocyclic a-helical peptides using disulfide, laetam, and diester linkages for biophysieal studies and dmg diseovery.

The structural diversity of macrocyclic a-helical peptides continues to expand with novel chemistiy methodologies. For example, a photoinduced 1,3-dipolar cycloaddition approach for macrocyclization has been introduced as illustrated by the pyrazoline-stapled p53 peptide 25 (Figure 9.8). Interestingly, a bis-thioether macrocyclized a-helical p53 peptide, 26, was determined to exhibit good cellular uptake when conjugated with a... 

Macrocyclic a-Helical Peptide Chemical Biology and Drug Design... 

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