Last Updated: 10/06/2024
Preclinical development of an antimalarial agent with a new mechanism of action
Objectives
A compound from the series, BRD5018, was selected as a development candidate and was demonstrated to have good drug-like properties. Early safety assessment with BRD5018 in rodents suggests that primary toxicities are monitorable and reversible. The purpose of this proposal is to complete the necessary studies to nominate BRD5018 for Phase I clinical trials.
Malaria is mosquito-borne disease that resulted in an estimated 212 million cases and 429,000 deaths in 2015. The lifecycle of Plasmodium parasites (the causative agent of malaria) involves a blood-, liver- and transmission-stage; however, most standard-of-care antimalarials target only the blood-stage parasites. Even though liver- and transmission-stage parasites do not cause malaria symptoms, prophylactic (ideally liver-stage-active) and transmission-blocking drugs are essential for the prevention of the disease and to protect vulnerable populations such as military personnel operating in endemic regions. The Broad Institute, in collaboration with Eisai Inc., has developed a series of antimalarial compounds that show excellent efficacy in malaria mouse models against blood-, liver- and transmission-stage parasites. Additionally, resistance is developing to current antimalarial therapies, and so there is an urgent need to develop medicines that disrupt parasites in unique ways, thus avoiding mechanisms that render existing drugs ineffective. It has been demonstrated that compounds from this series act via a new mechanism (inhibition of parasite protein synthesis) and as such represents an important development to combat antimalarial resistance. It is anticipated that BRD5018 will progress to the clinic, where it will provide relief to communities and military personnel in regions where resistance to current therapeutics is prevalent. Current approved antimalarial drugs used by the US military have side effects and associated drug resistance. BRD5018 represents an important addition to the antimalarial pipeline, both as a potential therapeutic and as a prophylactic agent. As such, the proposed project directly addresses a Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) topic area. The identification of novel and/or innovative malaria drug targets for blood and liver stage malaria parasites is a FY17 PRMRP area of encouragement. Successful implementation of this proposal will fulfill key steps on the path to first-in-man clinical studies for BRD5018 as an antimalarial agent and will clinically validate parasite phenylalanyl tRNA synthetase as a novel malaria drug target.
Jul 2018 — Jun 2021
$3.1M
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