Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix |
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| Institution: | 1. Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, IN 47405, USA;2. Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., Lawrence, KS 66047, USA;1. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA;1. Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary;2. Department of Inorganic and Analytical Chemistry, University of Debrecen, POB 21, H-4010 Debrecen, Hungary;3. Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary;4. Institute of Biology, Medicinal Chemistry and Biotechnology, The National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, GR-116 35 Athens, Greece |
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| Abstract: | Hsp90 is a molecular chaperone implicated in many diseases including cancer and neurodegenerative disease. Most inhibitors target the ATPase site in Hsp90’s N-terminal domain, with relatively few inhibitors of other domains reported to date. Here, we show that peptides derived from a short helix at the C-terminus of Hsp90 show micromolar activity as Hsp90 inhibitors in vitro. These inhibitors do not block the N-terminal domain’s ATP-binding site, and thus are likely to bind at the C-terminal domain. Substitutions and helix stapling were applied to demonstrate structure–activity relationships and improve activity. These helical peptides will help guide the design of a new class of inhibitors of Hsp90’s C-terminal domain. |
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| Keywords: | Peptides Stapled helices Protein–protein interactions Hsp90 Molecular chaperones |
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