Paired inhibition of falciparum merozoite invasion

The ongoing, indeed once again increasing, burden of malaria is well-recognized, as is the steadfast threat of drug resistance that drives discovery efforts for new antimalarials. Drug combinations to enhance efficacy and to thwart the emergence of resistance are now considered a requirement for antimalarial therapy. Elegant genetic and inhibitor studies have revealed the sequential multistep process of merozoite invasion into erythrocytes, and have identified as essential the linkage of highly conserved reticulocyte-like binding protein 5 (Rh5) to basigin, its red cell membrane protein receptor. This proposal explores the consequences of combining human anti-Rh5 monoclonal antibodies with small molecule inhibitors, against asexual falciparum malaria parasites in vitro. Selected monoclonals will target Rh5 epitope communities that are known to inhibit parasite growth. Small molecule choices will include representative inhibitors for every phase of merozoite invasion. Combinations will be evaluated for additivity, synergy or antagonism. Findings from these experiments will guide further studies.