EDITORIAL COMMENTARY
Taking a Bite Out of Mosquitoes: A New Drug to Block Transmission of Malaria Ravi Durvasula1,2 1
Chief of Medicine, New Mexico VA Health Care System and 2Center for Global Health, University of New Mexico School of Medicine, Albuquerque
(See the major article by Ojo et al on pages 275–84.)
Keywords.
malaria; Plasmodium falciparum; artemesinin resistance; drug discovery; gametocytes.
Received and accepted 15 July 2013; electronically published 28 November 2013. Correspondence: Ravi Durvasula, MD, Chief of Medicine, Raymond G. Murphy VA Medical Center, 1501 San Pedro Drive SE, Albuquerque, NM 87108 ([email protected]). The Journal of Infectious Diseases 2014;209:177–9 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
mefloquine, lumefantrine, or amodiaquine are first-line therapies for uncomplicated malaria in most endemic regions of the world. Such treatments can be highly effectivewith resolution of parasitemia when administered soon after onset. Although artemesinin-based therapies have proven successful in many trials across Africa and Southeast Asia, 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 from patients seen in clinics along the Thailand-Myanmar border.Furthermore,resistanceratesinWestern Cambodia were reported to be greater than 40 percent. Assays of parasite clearance were 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 of male 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
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Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
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
sporozoites. For this strategy to be effective, the drug would have to be widely bioavailable and have a long half-life, because release and persistence of gametocytes in humans occurs over a lengthy period of time. Through a strategy of N-methylation, Ojo et al developed compound 1294, which offers 8-fold increase in bioavailability after a single oral dose, when compared to precursors, and significantly prolonged serum half-life in a mouse model. Transmission studies using the mosquito, Anopheles stephensii, confirmed that insects feeding on blood that was pretreated with as little as 0.1 µM of compound 1294, had significantly reduced oocyst formation in the midgut, which would correlate with decreased capacity to transmit malaria. 178
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Taken together, the studies of Ojo et al offer a new direction in antimalarial therapy. Current chemotherapeutic regimens against P. falciparum are primarily directed at the asexual stages of the parasite (Figure 1) and provide treatment to already infected individuals. Drugs such as compound 1294 could be used in concert with current regimens, thereby permitting dual modes of attack against malarial parasites and sites of action within humans and mosquitoes. Furthermore, drugs that target gametocytes could address a critical stage in parasite evolution. The sexual phase of P. falciparum gives rise to mutant parasites that carry drug-resistant traits. Compounds that disrupt the parasite life cycle at this phase could, theoretically, reduce the
EDITORIAL COMMENTARY
burden of escape mutants and slow the evolution of parasite resistance when used in combination with schizonticidal agents. Hopefully, the next few years will witness an end to malaria. Efforts to reduce transmission via bed nets, targeted insecticides, and environmental management coupled with the latest advances in vaccines, even engineered insects that are incapable of transmitting parasites [5] could signal the end to this global menace. In the meantime, more effective drugs are desperately needed as resistance of P. falciparum to available agents spreads across the world. Let’s hope that the new class of compounds described by Ojo et al fits the bill and offers a new set of tools in the fight against malaria.
Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
Figure 1. Life cycle of parasites of the genus Plasmodium. The sexual phase of the parasite cycle, resulting in zygote formation, occurs in the mosquito, and exflagellation of male gametocytes, the immediate precursor to zygote formation, is the target of compound 1294. Source: CDC - DPDx/Alexander J. da Silva, PhD, and Melanie Moser. Public Health Image Library, image #3405 (http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/M-R/Malaria/body_ Malaria_il1.htm) (2002).
Notes
References
Financial support. This work was supported by The Bill and Melinda Gates Foundation. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
1. http://www.path.org/projects/malaria_control_ partnership.php. Accessed 25 June 2013. 2. The RTS, S Clinical Trials Partnership. A Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in African Infants. N Engl J Med 2012; 367: 2284–95. 3. Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemesinin-resistant malaria on
the western border of Thailand: a longitudinal study. Lancet 2012; 379:1960–6. 4. Ojo KK, Eastman RT, Vidadala RS, et al. Specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation. J Infect Dis 2013. 5. Fang W, Vega-Rodriguez J, Ghosh AK, et al. Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science 2011; 331:1074–7.
Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
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Taking a Bite Out of Mosquitoes: A New Drug to Block Transmission of Malaria Ravi Durvasula1,2 1
Chief of Medicine, New Mexico VA Health Care System and 2Center for Global Health, University of New Mexico School of Medicine, Albuquerque
(See the major article by Ojo et al on pages 275–84.)
Keywords.
malaria; Plasmodium falciparum; artemesinin resistance; drug discovery; gametocytes.
Received and accepted 15 July 2013; electronically published 28 November 2013. Correspondence: Ravi Durvasula, MD, Chief of Medicine, Raymond G. Murphy VA Medical Center, 1501 San Pedro Drive SE, Albuquerque, NM 87108 ([email protected]). The Journal of Infectious Diseases 2014;209:177–9 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
mefloquine, lumefantrine, or amodiaquine are first-line therapies for uncomplicated malaria in most endemic regions of the world. Such treatments can be highly effectivewith resolution of parasitemia when administered soon after onset. Although artemesinin-based therapies have proven successful in many trials across Africa and Southeast Asia, 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 from patients seen in clinics along the Thailand-Myanmar border.Furthermore,resistanceratesinWestern Cambodia were reported to be greater than 40 percent. Assays of parasite clearance were 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 of male 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
EDITORIAL COMMENTARY
•
JID 2014:209 (15 January)
•
177
Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
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
sporozoites. For this strategy to be effective, the drug would have to be widely bioavailable and have a long half-life, because release and persistence of gametocytes in humans occurs over a lengthy period of time. Through a strategy of N-methylation, Ojo et al developed compound 1294, which offers 8-fold increase in bioavailability after a single oral dose, when compared to precursors, and significantly prolonged serum half-life in a mouse model. Transmission studies using the mosquito, Anopheles stephensii, confirmed that insects feeding on blood that was pretreated with as little as 0.1 µM of compound 1294, had significantly reduced oocyst formation in the midgut, which would correlate with decreased capacity to transmit malaria. 178
•
JID 2014:209 (15 January)
•
Taken together, the studies of Ojo et al offer a new direction in antimalarial therapy. Current chemotherapeutic regimens against P. falciparum are primarily directed at the asexual stages of the parasite (Figure 1) and provide treatment to already infected individuals. Drugs such as compound 1294 could be used in concert with current regimens, thereby permitting dual modes of attack against malarial parasites and sites of action within humans and mosquitoes. Furthermore, drugs that target gametocytes could address a critical stage in parasite evolution. The sexual phase of P. falciparum gives rise to mutant parasites that carry drug-resistant traits. Compounds that disrupt the parasite life cycle at this phase could, theoretically, reduce the
EDITORIAL COMMENTARY
burden of escape mutants and slow the evolution of parasite resistance when used in combination with schizonticidal agents. Hopefully, the next few years will witness an end to malaria. Efforts to reduce transmission via bed nets, targeted insecticides, and environmental management coupled with the latest advances in vaccines, even engineered insects that are incapable of transmitting parasites [5] could signal the end to this global menace. In the meantime, more effective drugs are desperately needed as resistance of P. falciparum to available agents spreads across the world. Let’s hope that the new class of compounds described by Ojo et al fits the bill and offers a new set of tools in the fight against malaria.
Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
Figure 1. Life cycle of parasites of the genus Plasmodium. The sexual phase of the parasite cycle, resulting in zygote formation, occurs in the mosquito, and exflagellation of male gametocytes, the immediate precursor to zygote formation, is the target of compound 1294. Source: CDC - DPDx/Alexander J. da Silva, PhD, and Melanie Moser. Public Health Image Library, image #3405 (http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/M-R/Malaria/body_ Malaria_il1.htm) (2002).
Notes
References
Financial support. This work was supported by The Bill and Melinda Gates Foundation. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
1. http://www.path.org/projects/malaria_control_ partnership.php. Accessed 25 June 2013. 2. The RTS, S Clinical Trials Partnership. A Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in African Infants. N Engl J Med 2012; 367: 2284–95. 3. Phyo AP, Nkhoma S, Stepniewska K, et al. Emergence of artemesinin-resistant malaria on
the western border of Thailand: a longitudinal study. Lancet 2012; 379:1960–6. 4. Ojo KK, Eastman RT, Vidadala RS, et al. Specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation. J Infect Dis 2013. 5. Fang W, Vega-Rodriguez J, Ghosh AK, et al. Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science 2011; 331:1074–7.
Downloaded from http://jid.oxfordjournals.org/ at toledo hospital on May 3, 2015
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