Taking a Bite Out of Mosquitoes: A New Drug to Block Transmission of Malaria

Despite concerted control efforts and decades of research, malaria remains a global scourge and the most important parasitic disease of humans. Infections caused by the parasite Plasmodium falciparum exact a huge toll, largely in subSaharan Africa, where nearly a million children die annually from complications of malaria. Integrated campaigns such as The Malaria Control and Evaluation Program in Africa (MACEPA) have adopted comprehensive strategies including insecticide-impregnated bed nets, artemesininbased combination therapies, aggressive indoor insecticide spraying, and advanced diagnostics to reduce mortality in children by nearly 20 percent [1]. Such recent advances coupled with evolving prospects for a vaccine against malaria [2] suggest that the goal of malaria eradication may soon be attainable, using an arsenal of preventive practices. For now, chemotherapeutic measures remain the mainstay of malaria management. Currently, combination therapy with artemesinin derivatives and agents such as mefloquine, lumefantrine, or amodiaquine are first-line therapies for uncomplicated malaria in most endemic regions of the world. Such treatments can be highly effectivewithresolutionofparasitemiawhen administered soon after onset. Although artemesinin-based therapies have proven successful in many trials across Africa and SoutheastAsia, there are growing concerns about evolving resistance of P. falciparum to these agents. Recently, Phyo et al [3] reported an alarming increase in rates of artemesinin resistance amongst P. falciparum isolates frompatients seen in clinics along the Thailand-Myanmar border.Furthermore,resistanceratesinWestern Cambodia were reported to be greater than 40percent.Assays of parasite clearancewere correlated with genotypic changes in parasite populations and nearly two-thirds of the variation in parasite clearance over a 3-year period was attributable to genetic polymorphisms in populations of P. falciparum. Indeed, emergence of widespread artemesinin resistance in this region of the world underscores the pressing need to develop novel anti-malarial agents. In this issue of the Journal, Ojo et al [4] report a very exciting new prospect for drug treatment of P. falciparum. The investigators describe a new class of antimalarial compounds that target the sexual stage of Plasmodium (Figure 1), specifically the parasite’s calcium-dependent protein kinase 4 (CDPK4), a signaling molecule that is essential for exflagellation of male gametocytes. This step is a precursor to the fusion ofmale and female gametocytes, which results in zygote formation in the mosquito. The sexual phase of the Plasmodium life cycle is critical and represents a potential target for drugs that would ultimately abort transmission of parasites by mosquitoes to humans. Compound 1294, reported by Ojo et al is a synthetic inhibitor of Plasmodium CDPK4. The authors demonstrate convincingly that the synthetic CDPK4 inhibitor inhibits exflagellation of gametocytes and, by acting on a specific serine residue of the parasite, avoids cross-reactivity with mammalian kinase substrates. Furthermore, the mechanism by which this compound acts on parasites is cleverly elucidated, using transgenic lines of Plasmodium. By generating a mutant parasite with a modified target site for the enzyme, the authors demonstrate that EC50 exflagellation values are shifted relative to wild-type parasites exposed to the same inhibitor. Thus, both efficacy of compound 1294 and its mode of action are presented in this seminal article. Gametocytes of P. falciparum begin maturation in the mammalian host and are taken up during a mosquito’s blood meal (Figure 1). Fusion of the gametocytes and formation of a zygote occur in the arthropod. Therefore, a CDPK4 inhibitor, taken as a drug by a human, would disrupt the parasite life cycle within the insect and prevent formation of infectious sporozoites. For this strategy to be effective, the drug would have to be widely bioavailable and have a long half-life, because Received and accepted 15 July 2013. Correspondence: Ravi Durvasula, MD, Chief of Medicine, Raymond G. Murphy VA Medical Center, 1501 San Pedro Drive SE, Albuquerque, NM 87108 (ravi.durvasula@va.gov). The Journal of Infectious Diseases Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jit523