Hsp70 and Hsp27 Modulators

Our Recent publications in the Hsp70 and Hsp27 Field

Binding Site evaluation of C-terminal Hsc70 inhibitors Samantha S. Zaiter, Yuantao Huo, Haritha K. Sudhakar, Fong Ying Tiew, Hélène Lebhar, and Shelli R. McAlpine* in preparation

The two major cytosolic isoforms include the constitutive Hsc70 protein and the stress inducible Hsp72 protein, that share ~86% sequence identity. Hsc70 (HSPA8) is expressed under basal conditions in all tissues and carries out the folding and transport of newly synthesised proteins as well as the de-aggregation or degradation of misfolded proteins. Hsc70 is critical to cellular survival and knockout of this gene is lethal in mice.Both isoforms of Hsp70 collaborate with Hsp90 to fold to fold a majority of proteins in the eukaryotic cytoplasm under basal conditions and in diseases such as cancer.The Hsp40/Hsp70 complex binds to the unfolded protein, and the protein is partially folded by this complex.protein We have identifed 3 compounds (C1, SY7, and SY8) that bind to Hsp70 near the C-terminus. Residues were located in the disordered region of Hsc70 near the IEEVD region are the binding site of these three compounds, where selectivity and directionality of the inhibitors is critical in order to bind effectively and inhibt the interaction between Hsp70 and HOP.

De novo design, synthesis, and mechanistic evaluation of short peptides that mimic heat shock protein 27 activity

Jessica Kho^a, P. Chi Pham^a, Suhyeon Kwon^a, Alana Y. Huang^a, Joel P. Rivers^a, Huixin Wang^a, Heath Ecroyd^b, and W. Alexander Donald^a, Shelli R. McAlpine*^c V12 p713-719 2021 DOI: 10.1021/acsmedchemlett.0c0060

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 of 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 5-8 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.

Designing de novo small molecules that control Heat shock protein 70 within the chaperone machinery Samantha S. Zaiter, Yuantao Huo, Fong Ying Tiew, Jason E. Gestwicki, and Shelli R. McAlpine* J. Med. Chem. V62, p742-761, 2019 DOI: 10.1021/acs.jmedchem.8b01436

Protein-protein interactions (PPIs) regulate all signalling pathways for cellular function. Developing molecules that modulate PPIs through the interface of their protein surfaces has been a significant challenge and there has been little success controlling PPI’s through standard molecular library screening approaches. PPIs control the cell’s protein-folding machinery, and this machinery relies on a multiprotein complex formed with heat shock protein 70 (Hsp70). Described is the design, synthesis and biological evaluation of molecules aimed to regulate the interaction between two proteins that are critical to the protein-folding machinery: heat shock protein 70 (Hsp70) and co-chaperone heat shock organizing protein (HOP). We report the first class of compounds that directly regulate these two protein-protein interactions and inhibit protein folding events.

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Hsp70 and Hsp27 Modulators

Our Recent publications in the Hsp70 and Hsp27 Field

Shelli R. McALpine, PhD., Visiting Professor at University of California, Irvine and Handling Editor Bioorganic Chemistry (Elsevier) mcalpine@uci.edu, www.coachingstemmacademics.com