Designing the next generation of medicines for malaria control and eradication

Abstract

In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For those parts of the world where the existing combinations show less than optimal activity, the priority is to have activity against emerging resistant strains, and other criteria take a secondary role. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. In this paper, an outline definition of the ideal and minimally acceptable characteristics of the types of clinical candidate molecule which are needed (target candidate profiles) is suggested. In addition, the optimal and minimally acceptable characteristics of combination medicines are outlined (target product profiles). MMV presents now a suggested framework for combining the new candidates to produce the new medicines. Sustained investment over the next decade in discovery and development of new molecules is essential to enable the long-term delivery of the medicines needed to combat malaria.

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

“…www.pnas.org/cgi/doi/10.1073/pnas.1414221111series (7). Pharmacological and chemical optimization of one of these series, the dihydroisoquinolones (DHIQs), led to the selection of a clinical candidate, (+)-SJ733, for development as a fast clearance component (Target Candidate Profile 1; TCP1) of a single-exposure radical cure and prophylaxis (SERCaP) drug (4). Here, we present evidence that (+)-SJ733 acts on the recently recognized target PfATP4 (pfatp4; PFL0590c) (8) to give rapid clearance of the parasite in vivo by inducing eryptosis or senescence in parasite-infected erythrocytes.…”

“…Recent successes in antimalarial drug discovery and development have led to renewed hope for global eradication of malaria (2,3). Antimalarial drugs are a critical component of the eradication campaign, and single-dose regimens of cheap, safe, and efficacious drugs, which ideally also reduce transmission, are required (4). The discovery of agents that act rapidly against novel targets would greatly aid in the development of such drugs (5).…”

In vitro inhibition of Plasmodium falciparum early and late stage gametocyte viability by extracts from eight traditionally used South African plant species

“…However, the currently available set of chemotherapeutics is largely only capable of impairing development of early stage gametocytes. The goal of discovering a single drug targeting all malaria stages (Burrows et al, 2013) motivated the evaluation of the ability of plant extracts to inhibit both early and late stage gametocytes in vitro.…”

Discovering New Transmission-Blocking Antimalarial Compounds: Challenges and Opportunities

“…Four challenges associated with anti-malarial drugs relevant to a malaria eradication agenda have previously been outlined: 1) blocking disease transmission by targeting sexual blood stage development in humans; 2) elimination of liver-stages including preventing and/or eliminating relapse from hypnozoites; 3) developing chemical entities that overcome cross-resistance and 4) targeting vulnerable populations [5,15,16]. However, a provocative challenge to the above could be to prioritise blocking transmission as a primary objective, since this could provide an over-arching solution to achieve malaria elimination.…”

“…Dual-active compounds, i.e. single compounds that target both asexual blood stages and mature gametocytes equipotently, provide the possibility to consolidate several anti-malarial target candidate profiles (TCPs) into a single target product profile (TPP) (for full definition see Glossary) [5,15,16] but with increased risk of resistance development (Box 1). Combinations of more than one entity, one with asexual blood stage activity and one with transmission-blocking ability could decrease the risk of developing resistance, but are associated with increased development costs and pharmacological complexities.…”