Next Generation ELQs for Treatment and Once-Monthly Protection Against Malaria

/ Abstract The Medicines for Malaria Venture (MMV) recently published a “roadmap” for the types of medicines that are needed to support the long-term goal of malaria elimination and eradication. The roadmap consists of a wish list of target candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the anti-malarial target candidates and product profiles the MMV highlighted the need for identifying new rapid acting medicines for active case management while other drugs are needed for chemo-protection and chemo- prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver- stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex ELQ-300 selectively targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. Unlike atovaquone, ELQ-300 is a selective inhibitor of the Qi site of the targeted enzyme complex. With support from the NIH and US DOD we created a prodrug, ELQ-331, that is more effective in vivo due to improved oral bioavailability. This drug has been accepted by the MMV as a Preclinical Candidate for once-weekly dosing for disease prevention. We have now identified ELQ-596 with significantly improved intrinsic anti-plasmodial activity in vitro, enhanced efficacy in vivo in a mouse model of the disease and a more extended bloodstream half-life relative to its progenitor. This application seeks support for optimizing the structural features of ELQ-596 to provide a Next Generation of ELQs for once-monthly oral prophylaxis in humans. This would simplify the dosing regimen, improve compliance, decrease the dose and associated costs, and improve outcomes. Superior molecules will advance through a down-selection test cascade for assessment of selective potency and lack of mammalian cytotoxicity, metabolic stability, solubility in simulated intestinal fluids, resistance propensity and mode of action as well as efficacy against blood and liver stage malaria in mice. Prodrugs of superior molecules will be explored to assess for enhanced oral bioavailability and antimalarial performance over parent molecules. Scientists with expertise in the following areas make up the collaborative investigational team: medicinal chemistry, malaria, molecular parasitology, biochemistry, structural biology, and pharmacology. Project Number: 1R01AI182513-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Michael RISCOE (+1 co-PI) | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $587,318 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-U (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18251301A1