Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Abstract

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

Machine Learning Uses Chemo-Transcriptomic Profiles to Stratify Antimalarial Compounds With Similar Mode of Action

“…Asexual blood stage parasites treated with compounds with different MoAs show distinct and divergent transcriptomic responses ( Hu et al., 2009 ; Siwo et al., 2015 ; van der Watt et al., 2018 ). This has also been observed for immature gametocytes ( Ngwa et al., 2017 ; Ngwa et al., 2019 ; Reader et al., 2021 ), which implies that chemically-induced transcriptome responses can be detected for various life cycle stages of the parasite. The parasite’s transcriptome can therefore be mined to stratify compounds to specific MoAs.…”

“…Additionally, such compounds should have a novel mode of action (MoA) and will be used in combination with each other to lower the rate of resistance emergence ( Verlinden et al., 2016 ). Phenotypic whole-cell screening has successfully delivered thousands of hit compounds [validated hits ( Quancard et al., 2021 )] with nanomolar whole-cell activity against multiple life cycle stages of P. falciparum ( Plouffe et al., 2008 ; Gamo et al., 2010 ; Delves, 2012 ; Miguel-Blanco et al., 2017 ; Delves et al., 2018 ; Delves et al., 2019 ; Abraham et al., 2020 ; Reader et al., 2021 ). However, this process is not guided by any knowledge on a compounds’ MoA or target.…”

In Vivo Efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and In Vitro Activity of SQ109 Metabolites

“…In these organisms, one of the suggested mechanisms is again that the compound acts as a protonophore uncoupler and rapidly collapses the mitochondrial membrane potential [9][10][11]. In addition, as with the kinetoplastid parasites, SQ109 was also found to have potent in vitro activity against Plasmodium falciparum where it was shown to selectively inhibit mature gametocytes (stage IV/V), the stage responsible for transmission, with an IC50 value of 0.105 µM [13]. With the generation of an SQ109-resistant clone, mutations in One such example is the anti-tubercular drug candidate SQ109 [N-adamantan-2-yl-N'-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine] which has been found have potent activity against kinetoplastid parasites in vitro [7][8][9][10][11], but there have been no reports of its activity in vivo in any protozoa.…”

“…In these organisms, one of the suggested mechanisms is again that the compound acts as a protonophore uncoupler and rapidly collapses the mitochondrial membrane potential [9][10][11]. In addition, as with the kinetoplastid parasites, SQ109 was also found to have potent in vitro activity against Plasmodium falciparum where it was shown to selectively inhibit mature gametocytes (stage IV/V), the stage responsible for transmission, with an IC 50 value of 0.105 µM [13].…”

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

“…Pillar 2 of this strategy is to accelerate efforts toward the elimination of malaria and attainment of malaria-free status. All evidence shows the fact that malaria elimination will require new strategies not only to target the hepatic stage, the erythrocytic stage, and the gametocyte development stages to prevent transmission to vectors but also to target the sporogonic stages inside the vector to prevent transmission to a new human host ( 2 , 9 , 10 ). The hepatic and sporogonic stages of the malaria parasite have remained largely underexploited as antimalarial targets, due to the poorly understood biology of these life cycle stages and the inherent technical difficulties in studying them ( 10 , 11 ).…”