Hsp70 Protein Complexes as Drug Targets

Abstract

Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70’s interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, such as pro-folding, pro-degradation and pro-trafficking. Thus, a promising strategy may be to block protein-protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to those goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology.

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

“…Chaperone inhibitors are intended to block oncogenic or disease protein folding and function to sensitize cells to cellular stress generated by conventional chemotherapies (Neckers and Workman, 2012). HSP/C 70/90 are both attractive as therapeutic targets because they contain multiple sites amenable to drug targeting, including ATP cofactor-binding sites, client protein substrate sites, and protein-protein interfaces (PPIs), with cochaperones that facilitate client protein folding activity (Rérole et al, 2011;Assimon et al, 2013;Balaburski et al, 2013;Schlecht et al, 2013). Many HSP/C 90/70 inhibitors are indeed small molecule adenosine analogs that target the nucleotidebinding site (Chiosis et al, 2002;Dymock et al, 2004;Donnelly and Blagg, 2008;Williamson et al, 2009;Day et al, 2010;Budina-Kolomets et al, 2014).…”

Binding of Human Nucleotide Exchange Factors to Heat Shock Protein 70 (Hsp70) Generates Functionally Distinct Complexes in Vitro

“…Accordingly, Hsp70 has become an attractive drug target for neurodegenerative and hyperproliferative disorders (3,4). However, it is difficult to envision strategies for selectively inhibiting its pathobiology without impacting its essential roles (5,6). To help guide this process, there is an interest in better understanding how Hsp70 is recruited into its various functions.…”

“…A key insight into how Hsp70 might be able to "juggle" its multiple functions comes from studies on cochaperones (6). Cochaperones, including the J proteins and the nucleotide exchange factors (NEFs), interact with Hsp70 and guide its various activities.…”

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

“…One promising way to inhibit Hsp70's activity in cancer cells may be to target the chaperone's many allosteric sites [56,100]. This approach might be expected to avoid some of the problems of selectivity and potency associated with active site inhibitors.…”

“…It is important to note that the allosteric motions in Hsp70 are further regulated by binding to co-chaperones [56]. There are three major families of co-chaperones in the mammalian Hsp70 system: J proteins, nucleotide exchange factors (NEFs), and tetratricopeptide repeat (TPR) domain-containing proteins.…”