HSP70 and their co-chaperones in the human malaria parasite P. falciparum and their potential as drug targets

Abstract

As part of their life-cycle, malaria parasites undergo rapid cell multiplication and division, with one parasite giving rise to over 20 new parasites within the course of 48 h. To support this, the parasite has an extremely high metabolic rate and level of protein biosynthesis. Underpinning these activities, the parasite encodes a number of chaperone/heat shock proteins, belonging to various families. Research over the past decade has revealed that these proteins are involved in a number of essential processes within the parasite, or within the infected host cell. Due to this, these proteins are now being viewed as potential targets for drug development, and we have begun to characterize their properties in more detail. In this article we summarize the current state of knowledge about one particular chaperone family, that of the HSP70, and highlight their importance, function, and potential co-chaperone interactions. This is then discussed with regard to the suitability of these proteins and interactions for drug development.

Infected erythrocytes and plasma proteomics reveal a specific protein signature of severe malaria

“…Among the 29 quantified parasitic proteins, we identified HSP70 ( PF3D7_0917900 ), involved in protein refolding and the glycolysis protein enolase ( PF3D7_1015900 ). Parasitic chaperone proteins like HSP70 are parasite survival factors, counteracting several biological host reactions including fever, degradation or immune system response (Barth et al, 2022 ), and contribute to P. falciparum virulence (Shonhai and Blatch, 2021 ). The glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ; PF3D7_1462800 ) was quantified only in the SM groups (Dataset EV9 ), representing an indirect reflection of increased protein levels.…”

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

“…There is substantial evidence that PfHSPs are not only genuine drug targets but that they also carry highly druggable structural features for antimalarial drug discovery. 9 , 10 , 11 HSPs were discovered on the basis that their expression was significantly upregulated in response to physical, chemical, or physiological stress factors, and they were named according to their apparent molecular weight; for example, HSP70 (HSP70) is a 70 kDa protein. The major families of HSPs (HSP10, HSP40, HSP60, HSP70, HSP90, and HSP100) have now been shown to play essential roles in cell survival not only under stressful conditions but also under normal physiology, with many of them demonstrated to be molecular chaperones with both inducible and constitutive isoforms.…”

“… 44 PfHSP70-1 is an abundant chaperone of the parasite cytosol that is required for survival. 10 Known inhibitors of PfHSP70-1 include polymyxin B and (−)-epigallocatechin-3-gallate, both of which bind with high affinity (submicromolar) to the full-length protein and a nucleotide-binding domain (NBD) construct, suggesting that the primary bind site is the N-terminal ATPase domain ( Table 1 ). 28 , 29 Similarly, the phytocompound iso-mukaadial acetate inhibits the basal ATPase activity of PfHSP70-1, 30 while malonganenones, including malonganenone A, B, and C, and 1,4 naphthoquinones, particularly lapachol and its derivatives, have been reported to inhibit the protein aggregation suppression activity of PfHSP70-1 ( Table 1 ).…”

“… 87 , 89 , 90 Very limited information about small molecule inhibitors of PfHSP70-2 is available. 10 Using in vitro binding assays, four commercially available small molecule inhibitors with broad specificity to the HSP70 family members viz., gilvocarcin V, apoptozole, MKT-077, and VER-155008 91 , 92 , 93 , 94 were found to interact with PfHSP70-2. 68 All these small molecules exhibited very little difference in their binding affinities to PfHSP70-2 and GRP78, with the exception of VER-155008 which showed three-fold lesser binding affinity to PfHSP70-2 as compared to GRP78.…”

The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery

“…There have been relatively few small molecule inhibitor studies on PfJDP-PfHsp70 interactions in general ( Daniyan and Blatch, 2017 ; Barth et al, 2022 ), and even fewer studies that have identified specific small molecule inhibitors of the PfJDP-stimulated PfHsp70 ATPase activity or PfJDP-stimulated chaperone activity of PfHsp70s ( Dutta et al, 2021b ; Almaazmi et al, 2022 ). Small molecule compounds have been identified that inhibit the PfJDP-stimulated ATPase activity and not the basal ATPase activity of parasite-resident PfHsp70-1 (pyrimidinone DMT2264; Botha et al, 2011 ) and exported PfHsp70-x (malonganenone A; Cockburn et al, 2014 ).…”