Project Summary / 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 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 medicines 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. The MMV envisions that an injectable sustained-release formulation could be developed as a long- acting preventative providing up to 3 to 4 months of protection. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex, ELQ-300 targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. With support from the NIH and US DOD we have been successful in developing an oral formulation of prodrug ELQ-331 for use in humans for weekly prophylaxis against malaria, work that was performed in collaboration with SRI International. In the present application we seek NIH support for a comprehensive assessment of ELQ- 300 prodrugs for intramuscular injection to effect the sustained-release of drug from an oil depot (or other extended release matrix) into the host bloodstream at levels above the minimum effective concentration needed to block liver stage infection by infectious sporozoites. In collaboration with SRI International we will leverage our knowledge of ELQ-300 prodrug chemistry, crystallinity, stability, and solvent/vehicle solubility with their expertise in formulation design and optimization to identify the optimal ELQ-300 prodrug design that is paired with an optimal depot formulation to provide long-term protection of animals from sporozoite infection. Four different prodrug chemistries will be evaluated and compared, varying R-group chain length to optimize the physiochemical properties of the drug and to enhance solubility in vehicles and mixtures that are approved for human use. The overall goal is to develop a long-acting sustained release formulation of an ELQ-300 prodrug for chemo-protection against malaria.