Heat shock proteins as emerging therapeutic targets

Abstract

Chaperones (stress proteins) are essential proteins to help the formation and maintenance of the proper conformation of other proteins and to promote cell survival after a large variety of environmental stresses. Therefore, normal chaperone function is a key factor for endogenous stress adaptation of several tissues. However, altered chaperone function has been associated with the development of several diseases; therefore, modulators of chaperone activities became a new and emerging field of drug development. Inhibition of the 90 kDa heat shock protein (Hsp)90 recently emerged as a very promising tool to combat various forms of cancer. On the other hand, the induction of the 70 kDa Hsp70 has been proved to be an efficient help in the recovery from a large number of diseases, such as, for example, ischemic heart disease, diabetes and neurodegeneration. Development of membrane-interacting drugs to modify specific membrane domains, thereby modulating heat shock response, may be of considerable therapeutic benefit as well. In this review, we give an overview of the therapeutic approaches and list some of the key questions of drug development in this novel and promising therapeutic approach.

Figure 1

Elements of HSF-1 activation: potential drug targets. The figure contains the major elements of the activation of HSF-1, the major transcription factor leading to the induction of Hsp synthesis. The potential drug targets are the following: (1) cytoplasmic complex of HSF-1 and Hsp90; (2) HSF-1 translocation to the nucleus; (3) intranuclear distribution of HSF-1; (4) nuclear complex of HSF-1 and Hsp90; (5) retrotranslocation of HSF-1 to the cytoplasm. RalBP-1, Ral-binding protein-1; p23, cochaperone of Hsp90.

Figure 2

The tumor specificity of 17AAG, a geldanamycin analog inhibitor of Hsp90. 17AAG has a 100-times higher affinity towards the tumor-specific Hsp90 complexed by a large number of cochaperones than to the Hsp90 dimer, which is the predominant form of this chaperone in normal cells (Kamal et al., 2003; Lee et al., 2004).

Figure 3

Bimoclomol binds to the HSF-1 with a low affinity (Hargitai et al., 2003). Fitting of /R/-bimoclomol to the 3D model of the DNA-binding domain of human HSF-1. The SiteID, FlexX and the FlexiDock modules of the Sybyl package were used sequentially to identify the loop domain as the active center (yellow–red amino acids) of the DNA-binding domain of human HSF-1 and dock bimoclomol (green) into this site. The calculated binding energy for the /R/-bimoclomol was −26 kcal mol⁻¹. The backbone of the polypeptide is shown (purple).

Figure 4

Cascade of events from membrane defects to dysregulated stress protein response.