PUBLICATIONS

PUBLICATIONS

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

David A. Baker et al. 2017

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). (more…)

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 used to treat malaria. (more…)

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Kato N, et. al., Nature. 2016 Oct 20

ABSTRACT

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. (more…)

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

Le Bihan A et al., PLoS Med. 2016 Oct 4

ABSTRACT

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. (more…)

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

Miura K, Stone WJ, Koolen KM, Deng B, Zhou L, van Gemert GJ, Locke E, Morin M, Bousema T, Sauerwein RW, Long CA, Dechering KJ. 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 of test antibodies, and has been utilized widely in both non-clinical and clinical studies. (more…)

Analysis of the dose-dependent stage-specific in vitro efficacy of a multi-stage malaria vaccine candidate cocktail.

Boes A, Spiegel H, Kastilan R, Bethke S, Voepel N, Chudobová I, Bolscher JM, Dechering KJ, Fendel R, Buyel JF, Reimann A, Schillberg S, Fischer R. Malar J. 2016 May 17

ABSTRACT

BACKGROUND: The high incidence and mortality rate of malaria remains a serious burden for many developing countries, and a vaccine that induces durable and highly effective immune responses is, therefore, desirable. (more…)

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

Vos MW, Stone WJ, Koolen KM, van Gemert GJ, van Schaijk B, Leroy D, Sauerwein RW, Bousema T, Dechering KJ. 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 limited by the need to determine mosquito infection status by dissection and microscopy. (more…)

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

Lucantoni L, Silvestrini F, Signore M, Siciliano G, Eldering M, Dechering KJ, Avery VM, Alano P. 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 high predictive power are needed to identify new candidates. (more…)

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

D'Alessandro S, Corbett Y, Ilboudo DP, Misiano P, Dahiya N, Abay SM, Habluetzel A, Grande R, Gismondo MR, Dechering KJ, Koolen KM, Sauerwein RW, Taramelli D, Basilico N, Parapini S. 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. (more…)

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 all manifestations of the disease. (more…)

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

Boes A, Spiegel H, Voepel N, Edgue G, Beiss V, Kapelski S, Fendel R, Scheuermayer M, Pradel G, Bolscher JM, Behet MC, Dechering KJ, Hermsen CC, Sauerwein RW, Schillberg S, Reimann A, Fischer R. 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 of the disease. (more…)

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

Baragaña B et al., Nature. 2015 Jun 18

ABSTRACT

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. (more…)

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

Bolscher JM, Koolen KM, van Gemert GJ, van de Vegte-Bolmer MG, Bousema T, Leroy D, Sauerwein RW, Dechering KJ. 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. (more…)

Novel pantothenate derivatives for anti-malarial chemotherapy.

Pett HE, Jansen PA, Hermkens PH, Botman PN, Beuckens-Schortinghuis CA, Blaauw RH, Graumans W, van de Vegte-Bolmer M, Koolen KM, Rutjes FP, Dechering KJ, Sauerwein RW, Schalkwijk J. Malar J. 2015 Apr 18

ABSTRACT

BACKGROUND: A number of synthetic pantothenate derivatives, such as pantothenamides, are known to inhibit the growth of the human malaria parasite Plasmodium falciparum, by interfering with the parasite Coenzyme A (CoA) biosynthetic pathway. (more…)

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

Stone WJ, Churcher TS, Graumans W, van Gemert GJ, Vos MW, Lanke KH, van de Vegte-Bolmer MG, Siebelink-Stoter R, Dechering KJ, Vaughan AM, Camargo N, Kappe SH, Sauerwein RW, Bousema T. 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 and throughput. (more…)

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 each stage of infection in the vertebrate host. (more…)

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

D'Alessandro S, Silvestrini F, Dechering K, Corbett Y, Parapini S, Timmerman M, Galastri L, Basilico N, Sauerwein R, Alano P, Taramelli D. 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 stages, to measure gametocyte viability and drug susceptibility. (more…)