Title

De Novo Design, Synthesis, and Mechanistic Evaluation of Short Peptides That Mimic Heat Shock Protein 27 Activity

Publication Name

ACS Medicinal Chemistry Letters

Abstract

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.

Open Access Status

This publication is not available as open access

Volume

12

Issue

5

First Page

713

Last Page

719

Funding Sponsor

University of New South Wales

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Link to publisher version (DOI)

http://dx.doi.org/10.1021/acsmedchemlett.0c00609