Open AccessDe Novo Design, Synthesis, and Mechanistic Evaluation of Short Peptides That Mimic Heat Shock Protein 27 Activity
Author(s) -
Jessica Kho,
Paul Pham,
Suhyeon Kwon,
Alana Y Huang,
Joel P Rivers,
Huixin Wang,
Heath Ecroyd,
William A. Donald,
Shelli R. McAlpine
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00609
Subject(s) - hsp27 , heat shock protein , small molecule , peptide , biochemistry , peptide sequence , amino acid , chemistry , chaperone (clinical) , sequence (biology) , protein aggregation , gene , hsp70 , medicine , pathology
We report the first small molecule peptides based on the N-terminal sequence of heat shock protein 27 (Hsp27, gene HSPB1) that demonstrates chaperone-like activity. The peptide, comprising the SWDPF sequence located at Hsp27's amino (N)-terminal domain, directly regulates protein aggregation events, maintaining the disaggregated state of the model protein, citrate synthase. While traditional inhibitors of protein aggregation act via regulation of a protein that facilitates aggregation or disaggregation, our molecules are the first small peptides between 5 and 8 amino acids in length that are based on the N-terminus of Hsp27 and directly control protein aggregation. The presented strategy showcases a new approach for developing small peptides that control protein aggregation in proteins with high aggregate levels, making them a useful approach in developing new drugs.