Development of novel, biologically-active chemical entities towards antimalarial transmission-blocking drugs of the future

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

Malaria remains one of the leading causes of infant mortality in the developing world despite gains made over the last decade. Growing evidence of resistance to Artemisinin combination therapies (ACTs) threatens to reverse the gains made, underscoring the need for discovery of new drugs with novel targets and modes of action. One challenge to discovery of new potential drugs is, however, the constant arms race between drug-development and resistance acquisition of asexual malaria parasites, which have thus far always succeeded in evolving resistance to chemotherapy. This is in spite of efforts to find combinations of drugs having different pharmacological properties to make resistance emergence less likely. A relatively unexplored way to lessen the likelihood of resistance emergence is to target parasite transmission rather than replication. In the circulation of an infected individual, only 0.2-1% of parasites differentiate into gametocytes, the sexual forms responsible for transmission of malaria parasites to the mosquito for onwards infection. Targeting this natural bottleneck provides a tangible route to interrupt transmission whilst avoiding resistance selection because selection occurs in the mosquito not the human host. Towards discovery of transmission-blocking drugs of the future, researchers at Imperial College London, in collaboration with GlaxoSmithKline (GSK) and the Bill & Melinda Gates Foundation recently completed a major screen of ~100,000 potential antimalarial compounds in search of sexual stage-targeting chemical entities. 70,000 of these came from an entirely unscreened Global Health Chemical Diversity Library put together by Dundee University. The lead hits (20 or so) from this screen are entirely uncharacterised, non-toxic to human cells and have great potential to enter the antimalarial drug discovery pipeline. This PhD aims to investigate the chemical hits identified by the completed drug library screens at Imperial College and, working with industrial partner GSK to use medicinal chemistry and chemical biology to probe structure activity relationships (SAR) of each hit; define their mode of action, explore the pharmacokinetic and pharmacodynamic properties of each and build towards the development of rational leads that could become future antimalarial transmission-blocking drugs.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512540/1 01/10/2017 30/09/2021
2033046 Studentship EP/R512540/1 01/10/2017 30/09/2021 Sabrina Yahiya