Last Updated: 29/05/2025
Chemical genetic screening to identify synergistic inhibitors of malaria parasite cell cycle regulators
Objectives
This project aims to establish a novel experimental strategy which combines chemical and genetic approaches to identify lead compounds for malaria drug development. PfCRK4, an essential protein that possesses many features ideal for a drug target in malaria parasites, will be targeted.
Harvard T.H. Chan School of Public Health (HSPH), United States
Infection of humans with Plasmodium falciparum parasites results in significant morbidity and mortality. In the face of drug-resistance, it is imperative to identify new antimalarial lead compounds to ensure the success of control and eradication efforts. Screening parasites in vitro against large numbers of small molecules has led to the identification of several antimalarials that are now at an advanced stage of development, with forward chemical genomic approaches being powerfully employed to identify putative molecular targets.
Conditional protein expression approaches allow the identification of essential genes in the asexual cycle of Plasmodium parasites in red blood cells. In particular, the PfCRK4 gene has been identified as an essential regulator of DNA replication during asexual schizogony.
In this project, a new approach to identify small molecule inhibitors of essential genes, using parasite lines with conditional knockdown in specific target proteins, is proposed. Small molecule inhibitor screens will be carried out to identify compounds that synergize with PfCRK4 knockdown to inhibit parasite growth. Drug screens with kinase inhibitor libraries will be performed, biased to directly target PfCRK4, and structurally diverse bioactive libraries. The hypothesis is that these screens will simultaneously reveal both specific inhibitors of the PfCRK4 enzyme, and secondary inhibitors that target molecules in pathways closely related to PfCRK4 that are synergistic with the PfCRK4-specific inhibitors. The specificity of the compounds will be further established by a combination of reverse chemical genetics and forward chemogenomic approaches. Of great value will be lead compounds against the essential putative drug target PfCRK4 that may inform drug development. The team believes that the chemical genetic platform described here will simultaneously identify direct as well as secondary inhibitors of target pathways, important for the design of optimal drug combinations that might impede the emergence of drug-resistance.
Dec 2016 — May 2019
$437,073
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