Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties.

ABSTRACT: Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe³, Trp⁷, and Cba¹⁰) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at n

SUBMITTER: Partridge AW 

PROVIDER: S-EPMC6632053 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature