Author: Kumar Ongolu, Ravi ; Laidlaw, Michael G. ; Shanahan, Charles S. ; Khairnar, Pankaj V. ; Gupton, B. Frank ; Jin, Limei ; Aleshire, Sarah L. ; Donsbach, Kai O. ; Nelson, Ryan C.

MMV693183 is a promising antimalarial drug candidate that works for uncomplicated malaria treatment and resistance management. Herein, we report an efficient and highly regioselective synthesis of MMV693183. This novel synthetic method highlights a three-step route with an overall yield of 46% from readily available starting materials. The key to the success lies in (1) utilizing the subtle difference of the two amino groups in the starting material (S)-propane-1,2-diamine dihydrochloride without amino protection and (2) identifying the L-(+)-tartaric acid as the counter acid for the organic salt formation, yielding the desired regioisomer up to 100:0. The efficient and scalable three-step protocol operates under mild conditions with a high chemo/regioselectivity, providing effective access to MMV693183.

PLOS ONE

Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa

Article

Author: Sombié, Salif ; Bousema, Teun ; Sirima, Sodiomon B ; Nébié, Issa ; S Sermé, Samuel ; Bolscher, Judith M ; Soulama, Issiaka ; Guelbéogo, Wamdaogo M ; Dechering, Koen J ; Zongo, Soumanaba ; Ouédraogo, Nicolas ; B Henry, Noëlie ; T G Huijs, Tonnie ; Pietro, Alano ; Tiono, Alfred B ; S Coulibaly, Aboubacar ; Diarra, Amidou ; Collins, Katharine A

Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.

Nature CommunicationsQ1 · CROSS-FIELD

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Q1 · CROSS-FIELD

ArticleOA

Author: Barcelo, Catalina ; Baum, Jake ; Bolscher, Judith M ; Fidock, David A ; Bonnert, Roger V ; Trevitt, Graham ; Tumwebaze, Patrick K ; Hermkens, Pedro H H ; Pereira, Dhelio B ; Witkowski, Benoit ; Fernández, Benigno Crespo ; Rochford, Rosemary ; Dechering, Koen J ; Niles, Jacquin C ; Campo, Brice ; Munro, Justin ; Huijs, Tonnie ; Berning, Luuk ; Abla, Nada ; Aguiar, Anna C C ; Rubiano, Kelly ; Schalkwijk, Joost ; Demarta-Gatsi, Claudia ; Henderson, Rob W M ; Angulo-Barturen, Iñigo ; Llinás, Manuel ; Sanz, Laura M ; Churchyard, Alisje ; Pasaje, Charisse Flerida A ; Verhoef, Julie M J ; Jiménez-Diaz, María Belén ; Cooper, Roland A ; de Vries, Laura E ; Gamo, Francisco-Javier ; Jansen, Patrick A M ; Koolen, Karin M J ; Yeo, Tomas ; Kooij, Taco W A ; Roesch, Camille ; Striepen, Josefine ; Guido, Rafael V C ; Fuchs, Aline ; Wittlin, Sergio ; Rosenthal, Philip J ; Sauerwein, Robert W

AbstractDrug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Preclinical	NL	TropIQ Health Sciences BV	27 Sep 2022

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