Fungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

Hsp90 is a widely distributed and highly conserved molecular chaperone that is ubiquitously expressed throughout nature, being one of the most abundant proteins within non-stressed cells. This chaperone is up-regulated following stressful events and has been involved in many cellular processes. In Toxoplasma gondii, Hsp90 could be linked with many essential processes of the parasite such as host cell invasion, replication and tachyzoite-bradyzoite interconversion. A Protein-Protein Interaction (PPI) network approach of TgHsp90 has allowed inferring how these processes may be altered. In addition, data mining of T. gondii phosphoproteome and acetylome has allowed the generation of the phosphorylation and acetylation map of TgHsp90. This review focuses on the potential roles of TgHsp90 in parasite biology and the analysis of experimental data in comparison with its counterparts in yeast and humans.

Trypanosomiasis is caused by Trypanosoma species which affect both human and animal populations and pose a major threat to developing countries. The incidence of animal trypanosomiasis is on the rise. Surra is a type of animal trypanosomiasis, caused by Trypanosoma evansi, and has been included in priority list B of significant diseases by the World Organization of Animal Health (OIE). Control of surra has been a challenge due to the lack of effective drugs and vaccines and emergence of resistance towards existing drugs. Our laboratory has previously implicated Heat shock protein 90 (Hsp90) from protozoan parasites as a potential drug target and successfully demonstrated efficacy of an Hsp90 inhibitor in cell culture as well as a pre-clinical mouse model of trypanosomiasis. This article explores the role of Hsp90 in the Trypanosoma life cycle and its potential as a drug target. It appears plausible that the repertoire of Hsp90 inhibitors available in academia and industry may have value for treatment of surra and other animal trypanosomiasis.

Hsp90 (a.k.a. Hsp83) plays a significant role in the life cycle control of the protozoan parasite Leishmania donovani. Rather than protecting Leishmania spp. against adverse and stressful environs, Hsp90 is required for the maintenance of the motile, highly proliferative insect stage, the promastigote. However, Hsp90 is also essential for survival and proliferation of the intracellular mammalian stage, the amastigote. Moreover, recent evidence shows Hsp90 and other components of large multi-chaperone complexes as substrates of stage-specific protein phosphorylation pathways, and thus as likely effectors of the signal transduction pathways in Leishmania spp. Future efforts should be directed towards the identification of the protein kinases and the critical phosphorylation sites as targets for novel therapeutic approaches.

Plasmodium falciparum displays a large and remarkable variety of heat shock protein 40 family members (PfHsp40s). The majority of the PfHsp40s are poorly characterized, and although the functions of some of them have been suggested, their exact mechanism of action is still elusive and their interacting partners and client proteins are unknown. The P. falciparum heat shock protein 70 family members (PfHsp70s) have been more extensively characterized than the PfHsp40s, with certain members shown to function as molecular chaperones. However, little is known about the PfHsp70-PfHsp40 chaperone partnerships. There is mounting evidence that these chaperones are important not only in protein homoeostasis and cytoprotection, but also in protein trafficking across the parasitophorous vacuole (PV) and into the infected erythrocyte. We propose that certain members of these chaperone families work together to maintain exported proteins in an unfolded state until they reach their final destination. In this review, we critically evaluate what is known and not known about PfHsp40s and PfHsp70s.

Co-chaperones are well-known regulators of heat shock protein 90 (Hsp90). Hsp90 is a molecular chaperone that is essential in the eukaryotes for the folding and activation of numerous proteins involved in important cellular processes such as signal transduction, growth and developmental regulation. Co-chaperones assist Hsp90 in the protein folding process by modulating conformational changes to promote client protein interaction and functional maturation. With the recognition of Plasmodium falciparum Hsp90 (PfHsp90) as a potential antimalarial drug target, there is obvious interest in the study of its co-chaperones in their partnership in regulating cellular processes in malaria parasite. Previous studies on PfHsp90 have identified more than 10 co-chaperones in P. falciparum genome. However, many of them remained annotated as putative proteins as their functionality has not been validated experimentally. So far, only five co-chaperones, PfHop, Pfp23, PfAha1, PfPP5 and PfFKBP35 have been characterized and shown to interact with PfHsp90. This review will summarize current knowledge on the co-chaperones in P. falciparum and discuss their regulatory roles on PfHsp90. As certain eukaryotic co-chaperones have also been implicated in altering the affinity of Hsp90 for its inhibitor, this review will also examine plasmodial co-chaperones’ potential influence on approaches towards designing antimalarials targeting PfHsp90.

HIV-1 replication has been intensively investigated over the past 30 years. Hsp90 is one of the most abundant proteins in human cells, important in the formation and function of several protein complexes that maintain cell homeostasis. Remarkably, the impact of Hsp90 on HIV-1 infection has started to be appreciated only recently. Hsp90 has been shown to (a) promote HIV-1 gene expression in acutely infected cells, (b) localize at the viral promoter DNA, (c) mediate enhanced replication in conditions of hyperthermia and (d) activate the P-TEFb complex, which is essential for efficient HIV-1 transcription. Hsp90 has been implicated in buffering deleterious mutations of the viral core and in the regulation of innate and acquired immune responses to HIV-1 infection. Therefore, Hsp90 is an important host factor promoting several steps of the HIV-1 life cycle. Several small Hsp90 inhibitors are in Phase II clinical trials for human cancers and might potentially be used to inhibit HIV-1 infection at multiple levels.

Nematodes are amongst the most successful and abundant organisms on the planet with approximately 30 000 species described, although the actual number of species is estimated to be one million or more. Despite sharing a relatively simple and invariant body plan, there is considerable diversity within the phylum. Nematodes have evolved to colonize most ecological niches, and can be free-living or can parasitize plants or animals to the detriment of the host organism. In this review we consider the role of heat shock protein 90 (Hsp90) in the nematode life cycle. We describe studies on Hsp90 in the free-living nematode Caenorhabditis elegans and comparative work on the parasitic species Brugia pahangi, and consider whether a dependence upon Hsp90 can be exploited for the control of parasitic species.

This review highlights studies conducted in murine models to evaluate the efficacy of compounds targeting Heat shock protein (Hsp) 90 of malaria. Both advances achieved and limitations that exist are highlighted.