Abstract
Drug resistant Plasmodium falciparum parasites represent a major obstacle in our efforts to control malaria, a deadly vector borne infectious disease. This situation creates an urgent need to find and validate new drug targets to contain the spread of the disease. Several genes associated with the unfolded protein response (UPR) including Glucose-regulated Protein 78 kDa (GRP78, also known as BiP) have been deemed potential drug targets. We explored the drug target potential of GRP78, a molecular chaperone that is a regulator of the UPR, for the treatment of P. falciparum parasite infection. By screening repurposed chaperone inhibitors that are anticancer agents, we showed that GRP78 inhibition is lethal to drug-sensitive and -resistant P. falciparum parasite strains in vitro. We correlated the antiplasmodial activity of the inhibitors with their ability to bind the malaria chaperone, by characterizing their binding to recombinant parasite GRP78. Furthermore, we determined the crystal structure of the ATP binding domain of P. falciparum GRP78 with ADP and identified structural features unique to the parasite. These data suggest that P. falciparum GRP78 can be a valid drug target and that its structural differences to human GRP78 emphasize potential to generate parasite specific compounds.
Highlights
Malaria is a worldwide public health problem with an estimated 600,000 deaths per year[1]
The second construct encompassed the ATP binding domain and it will be referred as P. falciparum GRP78 (PfGRP78)-nucleotide-binding domain (NBD)
The results showed a large difference in the ADP and ATP binding affinities between Plasmodium and human GRP78 NBD proteins (Table 2)
Summary
Malaria is a worldwide public health problem with an estimated 600,000 deaths per year[1]. There is a constant need to identify and validate new antimalarial drug targets to sustain current disease control strategies. To meet this demand we explore the stress response pathway, which includes multiple chaperones that have been already validated as drug targets in other diseases, and have been suggested as potential new antiplasmodial drug targets[7,8]. The linkage between chaperone and ATPase activity provides the rationale to use inhibitors that bind to GRP78’s NBD, as pharmacological agents in order to combat diseases that rely on GRP78 function. Chemical targeting of the P. falciparum GRP78 chaperone appears to be a viable avenue to identify new drug leads against malaria
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