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Spergualin analogs as inhibitors of Hsp70‐CHIP protein‐protein interactions
Author(s) -
Smith Matthew,
Assimon Victoria,
Evans Christopher G,
Carolan James P,
Gestwicki Jason E
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb106
Subject(s) - hsp70 , ubiquitin ligase , regulator , chaperone (clinical) , microbiology and biotechnology , ubiquitin , protein folding , chemistry , hsp90 , plasma protein binding , in vitro , heat shock protein , natural product , proteasome , proteostasis , computational biology , biology , biochemistry , gene , medicine , pathology
The molecular chaperone, heat shock protein 70 (Hsp70), is an essential regulator of protein homeostasis that has roles in both primary folding and clearance of misfolded proteins. Thus, Hsp70 is thought to make triage decisions and direct the fate of its protein substrates. Several studies have suggested that it is the interaction between Hsp70 and a network of co‐chaperone proteins that determines how its substrates are processed. For example, binding of Hsp70 to the E3 ubiquitin ligase, CHIP, is thought to guide Hsp70‐bound substrates to the proteasome. However the mechanism governing this fate decision remains unresolved. We have recently discovered that the natural product, Spergualin, directly antagonizes the protein‐protein interaction between Hsp70 and CHIP. To improve the potency and stability of this promising chemical scaffold, we developed a new, combinatorial synthetic route that facilitates access to spergualin analogs. These efforts have yielded a more stable analog that potently inhibits the Hsp70‐ CHIP interaction. We anticipate that these inhibitors will be useful for probing the roles of the Hsp70‐CHIP complex in directing protein triage in vitro and in vivo.