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- W2023200370 abstract "•The current biological strategy supporting the discovery of new antimalarials at the Medicines for Malaria Venture (MMV) is described. •Biological assays underpinning the discovery of drugs that will lead to malaria eradication are reviewed. •Major limitations in the identification of new anti-relapse drugs are presented. •The way towards new molecules that will block malaria transmission is described. •A three-level risk scale for the development of resistance to antimalarials is proposed. Malaria is still considered a deadly scourge in Africa, Asia, and South America despite improved vector control and curative treatments with new antimalarial combinations. The next challenge is to work towards disease eradication. To achieve this goal it is crucial to develop, validate, and integrate biological assays into test cascades that align with the key target product profiles. For anti-relapse, a parent molecule should kill hypnozoites or cause activation of Plasmodium vivax liver stages. For transmission blocking, dual equal-activity antimalarials killing both the asexual and the sexual parasite stages in human blood are favored. Finally, by assessing cross resistance and generating drug resistance in the laboratory, it is expected that new medicines with acceptable resistance profiles will be forthcoming. Malaria is still considered a deadly scourge in Africa, Asia, and South America despite improved vector control and curative treatments with new antimalarial combinations. The next challenge is to work towards disease eradication. To achieve this goal it is crucial to develop, validate, and integrate biological assays into test cascades that align with the key target product profiles. For anti-relapse, a parent molecule should kill hypnozoites or cause activation of Plasmodium vivax liver stages. For transmission blocking, dual equal-activity antimalarials killing both the asexual and the sexual parasite stages in human blood are favored. Finally, by assessing cross resistance and generating drug resistance in the laboratory, it is expected that new medicines with acceptable resistance profiles will be forthcoming. non-dividing sexual forms of Plasmodium parasites that differentiate from asexual replicative forms in the blood of the host. Immature gametocyte stages I, II, and III are the precursors of the mature stages IV and V; the latter stage is transmitted to the mosquito midgut during a blood meal and then generates male and female parasite gametes. patients carrying mutations in the gene encoding for G6PD suffer from severe hemolysis when treated with the 8-aminoquinoline class of antimalarials and in particular with primaquine. The current hypothesis is that the primaquine metabolite responsible for the anti-hypnozoite activity would trigger massive lysis of the host erythrocytes in addition to the one due to the burst of parasites after the completion of every proliferative cycle (48 h for P. falciparum) in patient blood. key phase of the drug discovery process through which each single small molecule of large libraries (hundreds of thousands to millions of compounds) is tested at a given concentration (1–10 μM) for its capacity to inhibit purified enzymes (target-based screening) or to kill cells/parasites/bacteria (phenotypic screening). These high-throughput assays require the simultaneous analysis of many compounds, and therefore microtiter plates with up to 1536 wells have been developed and are routinely filled with reagents by automated devices to test compounds. non-dividing liver forms of Plasmodium vivax and possibly Plasmodium ovale that stay quiescent (‘dormant’, from Greek hypnos) following the infection of host hepatocytes by sporozoites. These parasite forms stay small (∼2 μm in diameter) and have a rounded shape, in contrast to the developing liver forms that produce schizonts (>10 μm in diameter). Hypnozoites can exit dormancy anywhere between a few weeks and several months after the patient is cured of symptomatic malaria (proliferative stage in the blood). The reasons for its quiescence and activation are not known, and its biology is barely understood. in the laboratory, incubation of antimalarials or drug candidates with various amounts of parasites (inocula) can lead to recrudescence after several days. This adaptation to growth in the presence of the drug depends on the capacity of the parasite to accumulate mutations leading to a modification of its drug targets or drug efflux pumps. The occurrence of mutated parasites correlates with the number of genomes (parasites) in the inoculum. The lower the inoculum allowing the appearance of a resistant mutant, the more the drug is assessed as inducing resistance. The MIR is the minimum necessary to produce resistance and is used to attribute a risk level to the molecule that is tested (a MIR of 105 parasites is a high risk, 107 a medium risk, and 109 a low risk). product development partnership organization created in 1999 with the mission to discover, develop, and deliver safe, efficient, and inexpensive new antimalarials in endemic countries such as those in Africa, Asia, and South America. Currently, 70 staff members work in tight collaboration with more than 300 academic and industrial partners around the world to achieve such a mission. For several years now, and in conjunction with many members of the antimalarial community, the objective is to fulfill the eradication agenda. the ultimate proliferative Plasmodium form that develops in the midgut of the mosquito (Anopheles) and that contains thousands of sporozoites, the host liver infective forms. precursor parasite form of the oocyst that develops after the zygote is formed and that invades the mosquito midgut. The most striking features of this parasite form are that it develops an apical complex and is highly motile. The ookinete and the zygote are the only two Plasmodium forms which are diploid. one of the rodent parasites that is currently used to test new compounds in preclinical mouse models. a parasite that infects monkeys (e.g., Rhesus monkeys) and that produces dormant forms in the liver of its host similarly to those produced in humans by Plasmodium vivax, its closest neighbor in the phylogenetic tree of Plasmodium spp. one of the five human unicellular eukaryotic parasites (with P. vivax, P. ovale, Plasmodium malariae, and Plasmodium knowlesi). antimalarial of the 8-aminoquinoline chemical class that was discovered by the US army nearly 60 years ago. The drug is administered daily for 14 days to clear the liver of patients from P. vivax hypnozoites and provide a radical cure of patients by avoiding relapses. The current hypothesis is that a transient metabolite of primaquine formed in the human liver kills hypnozoites and developing liver forms of P. vivax extremely rapidly. an assay developed by the group of D. Ménard in Cambodia to synchronize P. falciparum cultures and study specifically the action of endoperoxides on both artemisinin-sensitive and -resistant clinical isolates. So far this assay is the only one that has led to the characterization of the artemisinin resistance phenotype in vitro. a target product profile that has been defined to guide the discovery and development of the next-generation antimalarials that will protect vulnerable populations from infection by Plasmodium spp. a target product profile designed to guide the discovery and development of new combination therapies that will be administered to patients as a single dose, curing them from all malaria infections as well as providing protection against post-treatment reinfection. a method of feeding mosquitoes through an artificial membrane (parafilm) in a device filled with human blood in the absence or presence of compounds. This assay is used to assess the transmission-blocking potential of compounds in the drug discovery and development pipeline. Plasmodium forms that are released in the hemolymph and the salivary glands of the mosquito following the rupture of the oocyst membrane, and that infect the hepatocytes of the host, before evolving into replicative schizonts that ultimately liberate the erythrocyte infective forms, the merozoites. a new generation 8-aminoquinoline that will replace primaquine with a better efficacy and safety profile. Currently in Phase II clinical trial the drug is expected to be a single-dose treatment that will eliminate P. vivax hypnozoites from the liver of the host. pharmacodynamics, pharmacokinetics, and safety parameters that a drug candidate should exhibit to fulfill the radical cure or prophylaxis criteria. all the desired attributes of the final drug or drug combination, including pharmacodynamics, pharmacokinetic, safety and non-biological properties, including cost, stability, dosage, etc." @default.
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- W2023200370 date "2014-10-01" @default.
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- W2023200370 title "Defining the biology component of the drug discovery strategy for malaria eradication" @default.
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- W2023200370 doi "https://doi.org/10.1016/j.pt.2014.07.004" @default.
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