Abstract
Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.
Highlights
The most important obligate parasites that infect humans are mainly from the kinetoplastida and apicomplexa kingdoms
It has been suggested that a third of the T. brucei proteome undergoes at least a two-fold difference in abundance for parasites cultured in blood stream form (BSF), representing the mammalian host stage versus parasites cultured at the procyclic form (PCF), the latter representing conditions that prevail within the insect vector [12,13,14]
Heat shock protein 90 (Hsp90) is composed of an N-terminal domain (NTD) that serves as the ATP binding site, which in turn is linked to the middle domain (MD) through a charged linker segment [20]
Summary
The most important obligate parasites that infect humans are mainly from the kinetoplastida and apicomplexa kingdoms. It has been suggested that a third of the T. brucei proteome undergoes at least a two-fold difference in abundance for parasites cultured in blood stream form (BSF), representing the mammalian host stage versus parasites cultured at the procyclic form (PCF), the latter representing conditions that prevail within the insect vector [12,13,14]. This suggests that the protein folding machinery of obligate parasites needs to be adaptable to the demands of a life characterized with dynamic physiological changes. It has been reported that Hsp is important for the motility and infectivity of sporozoites of the malarial agents, Plasmodium vivax [18]
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