A high throughput screen for next-generation leads targeting malaria parasite transmission

Abstract

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies–Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites

“…This pronounced preference for late stage gametocytes is noteworthy, as most antimalarial compounds tend to show greater activity against the early stages with a loss in activity against late stage gametocytes (Peatey et al, 2012;Duffy and Avery, 2013). Thus the sub-nanomolar activities (IC 50 0.4-0.7 nM) of the sulfonamides 13-17 and 19, and the aryl amide 28 against late stage gametocytes, as compared to the micromolar activities of most other compound classes (Delves et al, 2018) are striking.…”

Structure–Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes

“…16 Recently, some of us reported the use of the DGFA to screen a 70,000-compound Global Health Chemical Diversity Library (GHCDL) from the University of Dundee. 17 The study represented the first example of a HTS campaign for the discovery of transmission-blocking agents carried out on a non-biased chemical library where transmission was the primary filter.…”

Natural Products: A Potential Source of Malaria Transmission Blocking Drugs?

“…Some natural compounds exhibit a TCP-5 activity profile while others have dual activity with additional potency against asexual parasites (defined with both TCP-1 and TCP-5 activity). The low hit rates of the synthetic compounds against sexual stage Plasmodium parasites [40][41][42][43], motivates expansion of the search for transmission-blocking drugs to natural products. This is justified particularly since their diverse chemical space and wide range of pharmacophores could lead to identification of novel lead compounds and associated targets in the parasite and as such avert existing drug resistance challenges.…”