The antimalarial screening landscape—looking beyond the asexual blood stage

Sabrina Yahiya,Ainoa Rueda-Zubiaurre,Michael J Delves,Matthew J Fuchter,Jake Baum

doi:10.1016/j.cbpa.2019.01.029

Abstract

In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antimalarials. One approach gaining increased interest is the potential of designing novel drugs that target parasite passage from infected individual to feeding mosquito and back again. Action of such therapeutics is geared much more at the population level rather than just concerned with the infected individual. The search for novel drugs active against these stages has been helped by improvements to in vitro culture of transmission and pre-erythrocytic parasite lifecycle stages, robotic automation and high content imaging, methodologies that permit the high-throughput screening (HTS) of compound libraries for drug discovery. Here, we review recent advances in the antimalarial screening landscape, focussed on transmission blocking as a key aim for drug-treatment campaigns of the future.

Highlights

Incredible progress has been made in reducing the global malaria burden since the declaration of the UN Millennium Development Goals in 2000
In recent years, progress has stalled, with incidence and death rates from malaria no longer declining [1]., Commitment to these goals triggered a spike in global funding and interest, resulting in an increased implementation of artemisinin combination therapies (ACTs), insecticide treated bed nets (ITNs) and indoor residual spraying (IRS) which was pivotal in addressing the global burden of malaria disease [2]
Many groups active in antimalarial drug discovery, coordinate their work within a framework of molecule type [target candidate profiles (TCP)], meaning the lifecycle stage which is compromised by the drug, and medicine class (target product profiles (TPP)], the final drug formulation defined as a combination of Target Candidate Profiles (TCP), developed by the not-for-profit Medicines for Malaria Venture, MMV [6] (Table 1)

Summary

Introduction

Incredible progress has been made in reducing the global malaria burden since the declaration of the UN Millennium Development Goals in 2000. In recent years, progress has stalled, with incidence and death rates from malaria no longer declining [1]., Commitment to these goals triggered a spike in global funding and interest, resulting in an increased implementation of artemisinin combination therapies (ACTs), insecticide treated bed nets (ITNs) and indoor residual spraying (IRS) which was pivotal in addressing the global burden of malaria disease [2]. Its derivatives and partner drugs [3] and mosquito resistance to insecticides are, key challenges to get reduction of malarial incidence back on track. One long-sought goal for optimal treatment formulation is the administration of a Single Encounter Radical Cure and Prophylaxis (SERCaP), removing blood parasitemia and the longer-lived parasite reservoir from patients for both radical cure and elimination of future transmission, all in one go [5]. Drug Discovery by screening In recent years, great emphasis has been placed on highthroughput screening (HTS) of large compound libraries, www.sciencedirect.com

Next Generation Therapeutics

Conclusions

38. Sinden RE