TropIQ-led collaboration develops novel malaria candidate drug

A molecule once designed to cure the skin disease psoriasis appears to be particularly effective against malaria. The antimalarial properties were revealed thanks to one researcher’s inspired hunch when the psoriasis drug discovery programme came to a dead end. The candidate drug offers considerable potential for combating this infectious disease. Full press release here en…

Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum

Schalkwijk et al., Sci. Transl. Med 2019 Sept 19 ABSTRACT Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds…

Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases

Miglianico M. et al., PNAS 2018 July 02 ABSTRACT Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented…

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

Vallone et al., Eur J Med Chem. 2018 Mar 10 ABSTRACT Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection…

Modelling mosquito infection at natural parasite densities identifies drugs targeting EF2, PI4K or ATP4 as key candidates for interrupting malaria transmission

Dechering KJ. et al., Sci. Rep. 2017 Dec 15 ABSTRACT Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that are substantially higher than observed…

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission

Baker DA. et al., Nat Commun. 2017 Sep. 5 ABSTRACT To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparumcyclic GMP-dependent protein kinase (PfPKG).

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

Paquet T. et al., Sci Transl Med. 2017 Apr 26 ABSTRACT As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs…

An inter-laboratory comparison of standard membrane-feeding assays for evaluation of malaria transmission-blocking vaccines.

Miura K. et al.,Malar J. 2016 Sep 9 ABSTRACT BACKGROUND: An effective malaria transmission-blocking vaccine may play an important role in malaria elimination efforts, and a robust biological assay is essential for its development. The standard membrane-feeding assay (SMFA) for Plasmodium falciparum infection of mosquitoes is considered a “gold standard” assay to measure transmission-blocking activity…

A semi-automated luminescence based standard membrane feeding assay identifies novel small molecules that inhibit transmission of malaria parasites by mosquitoes.

Vos MW. et al., Sci Rep. 2015 Dec 21 ABSTRACT Current first-line treatments for uncomplicated falciparum malaria rapidly clear the asexual stages of the parasite, but do not fully prevent parasite transmission by mosquitoes. The standard membrane feeding assay (SMFA) is the biological gold standard assessment of transmission reducing activity (TRA), but its throughput is…

A simple and predictive phenotypic High Content Imaging assay for Plasmodium falciparum mature gametocytes to identify malaria transmission blocking compounds.

Lucantoni L. et al., Sci Rep. 2015 Nov 10 ABSTRACT Plasmodium falciparum gametocytes, specifically the mature stages, are the only malaria parasite stage in humans transmissible to the mosquito vector. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria and tools allowing the screening of large compound libraries with…

Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity.

D’Alessandro S. et al., Antimicrob Agents Chemother. 2015 Sep ABSTRACT The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities.

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.

Phillips MA et al., Sci Transl Med. 2015 Jul 15 ABSTRACT Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against…

Analysis of a Multi-component Multi-stage Malaria Vaccine Candidate–Tackling the Cocktail Challenge.

Boes A, et al., PLoS One. 2015 Jul 6 ABSTRACT Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission…

A combination of new screening assays for prioritization of transmission-blocking antimalarials reveals distinct dynamics of marketed and experimental drugs.

Bolscher JM. et al., J Antimicrob Chemother. 2015 May ABSTRACT OBJECTIVES: The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmission-blocking molecules.

A scalable assessment of Plasmodium falciparum transmission in the standard membrane-feeding assay, using transgenic parasites expressing green fluorescent protein-luciferase.

Stone WJ. et al., J Infect Dis. 2014 Nov 1 ABSTRACT BACKGROUND: The development of drugs and vaccines to reduce malaria transmission is an important part of eradication plans. The transmission-reducing activity (TRA) of these agents is currently determined in the standard membrane-feeding assay (SMFA), based on subjective microscopy-based readouts and with limitations in upscaling…

Targeting Plasmodium PI(4)K to eliminate malaria.

McNamara CW et al., Nature. 2013 Dec 12 ABSTRACT Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at…

A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection.

D’Alessandro S. et al., J Antimicrob Chemother. 2013 Sep ABSTRACT OBJECTIVES: Plasmodium gametocytes, responsible for malaria parasite transmission from humans to mosquitoes, represent a crucial target for new antimalarial drugs to achieve malaria elimination/eradication. We developed a novel colorimetric screening method for anti-gametocyte compounds based on the parasite lactate dehydrogenase (pLDH) assay, already standardized for asexual…