The emergence and spread of artemisinin-resistant plasmodium falciparum in Southeast Asia is a compelling reminder to develop new drugs for malaria prophylaxis and treatment. Drugs that target pre-erythrocytic stages are an essential component of the anti-malarial effort because a decrease in liver infection by sporozoites significantly reduces severity and incidence of malaria. Existing anti-malarial that target pre-erythrocytic stages, such as primaquine, tafenoquine and atovaquone, have significant side-effects or are expensive. Therefore, there is an acute need for novel drugs that target pre-erythrocytic stages.
Rutgers researchers have chemically and biologically validated that P. falciparum cGMP dependent protein kinase (PfPKG) is required for the parasite’s liver cycle in the pre-erythrocytic stage. The lead compounds of PfPKG inhibitors have been developed and synthesized by optimizing the existing tri-substituted pyrolle, and the experiment shows that the inhibitor can prevent sporozoite infection and significantly delay the appearance of pathology-causing erythrocytic stages in mouse models of malaria infection.
Rutgers researcher are actively attempting to obtain structural information on the lead bound to PfPKG, using cryoEM and X-ray crystallography. The information can be used to inform and assist in the rational optimization of the lead PfPKG inhibitor to achieve greater potency, selectivity and activity in whole-cells.
- Novel inhibitors (targeting PfPKG) for “artemisinin-resistant malaria”
- Targeting pre-erythrocytic stages
- A drug to treat malaria as well as “artemisinin-resistant malaria”
Intellectual Property & Development Status: Patent pending and patent publication: PCT/US2020/029385. Available for licensing and/or research collaboration.