Discovery and Development of Novel Antimalarial Drugs

About This Grant

ABSTRACT The overall aim of this application is to develop a new class of antimalarials targeting PfGARP for use as parenteral therapy for severe falciparum malaria in direct response to MMV’s TPP-1-“For severe malaria, a parenteral formulation of a single fast-acting TCP-1 would be appropriate” (asexual stage agent) 1. Plasmodium falciparum is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing almost one-half of a million children in sub-Saharan Africa each year. The spread of parasites resistant to the artemisinin family of compounds threatens recent progress achieved by antimalarial campaigns and underscores the urgent need to identify new anti-malarial drugs. In recent work 5, we discovered PfGARP, a vaccine candidate found only in P. falciparum. PfGARP is located on the exofacial surface of iRBCs and antibodies to the highly invariant carboxyl terminal of PfGARP kill parasite in culture in the absence of immune effector molecules (complement) or cells- thus the remarkable anti-parasite effect of anti-PfGARP results from antibody binding alone. This is further supported by the killing effect of recombinant mAb and its rec monovalent Fab that target aa 443-459 of PfGARP. The Scientific Premise of this application that PfGARP is a high value druggable target is based on: 1) its surface expression on iRBCs, 2) its absence of amino acid homology with host proteins, 3) its absence of significant sequence variation in over 3,000 field isolates sequenced, 4) the requirement for PfGARP for in vivo survival, and 5) the ability of antibody binding to PfGARP to kill essentially all parasites within 12-24 hours. In the current proposal, we will: 1) conduct a targeted, high-throughput drug screen to discover drugs which mimic the lethal activity of antibodies recognizing PfGARP, 2) optimize and down select these candidates, and 3) validate these new drug candidates in a humanized mouse model of P. falciparum.