Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Abstract

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC 50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

Synthesis and Initial Evaluation of YM-08, a Blood-Brain Barrier Permeable Derivative of the Heat Shock Protein 70 (Hsp70) Inhibitor MKT-077, Which Reduces Tau Levels

“…MKT-077 analogues have been reported to modestly inhibit ATP hydrolysis, using a model Hsp70 system that includes yeast Hsp70 (Ssa1) and the stimulatory co-chaperone, Hlj1. 18,35 Using an identical assay system, we found that YM-08 also partially inhibited ATP turnover ( Figure 4A). Interestingly, YM-08 only inhibited the Hlj1-stimulated ATPase activity, with minimal effect on the intrinsic ATPase activity of Ssa1 ( Figure 4A).…”

Cysteine‐capped gold nanoparticles suppress aggregation of proteins exposed to heat stress

“…Therefore, the most likely explanation is that the AuNPs independently protected MDH from the effect of thermal stress, thus complementing the function of hHsp70. As the activity of Hsp70 protein is inhibited by several small molecules and some of these have been characterized (21,22). Thus, it is important to note that AuNPs did not inhibit the activity of hHsp70, and this confirms that AuNPs may not adversely affect the action of the protein folding machinery of the cell, further affirming their safety.…”

“…Various small molecules are known to modulate the function of Hsp70 molecular chaperones (21,22). We were curious to understand the effect of AuNPs on the chaperone function of hHsp70.…”

A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax

“…Recently, Plasmodium encoded chaperones have been shown to be important for its growth and survival within the host [35,36]. The proteome profile of clinical isolates, which consists mostly of abundant parasite proteins, contains seven Pf -encoded chaperones and three Pv -encoded chaperones, indicating their importance in clinical parasite isolates.…”

“…In addition, Hsp70-I (cytosolic Hsp70), Hsp70-x (another cytosolic Hsp70), and two different RESA are also expressed. Inhibitors of Hsp70-I activity have been shown to inhibit parasite growth and RESA have been shown to be critical for maintenance of the infected erythrocyte cytoskeleton during heat stress [36,37]. This implies that the clinical isolates of Pf express proteins that enable them to tide over thermal stress such as febrile episodes in the patient.…”