The development of novel 4-aminoquinolines as therapeutics against multi-drug resistant Plasmodium falciparum - Project Summary Malaria caused over 619 thousand deaths and resulted in the infection of more than 247 million individuals in 2021. Emergence of resistance to single and combination frontline-therapeutics have been reported in endemic areas and threatens the efforts to eradicate the disease. We believe that continued development of 4- aminoquinolines holds immense un-tapped therapeutic and clinical potential to overcome emerging multi-drug resistant (MDR) strains of Plasmodium falciparum (Pf), the deadliest species of malaria parasite. To this end, I developed an initial compound screen, inspired from previous work in our lab, which produced two separate compounds, MH01-128 and MH01-173, both exhibiting low nanomolar antiplasmodial activity in an in vitro proliferation assay against MDR Pf. In addition, the two compounds demonstrated parasite clearance in a murine malaria model; however, both compounds suffer from metabolic instability, measured in pooled murine liver microsomes. To increase metabolic stability of MH01-173, I performed an iterative structure activity relationship study that produced the compound MH02-060. This next-generation compound exhibited enhanced metabolic stability and produced a non-recrudescence dose without change to intrinsic anti-plasmodial activity. The work I propose hereafter aims to further develop MH02-060 as an antimalarial. In Aim 1 I will use an iterative medicinal chemistry approach to select for compounds that maintain antiplasmodial activity versus MDR Pf, favorable pharmacokinetic properties, and superior in vivo efficacy. In Aim 2, potential targets of MH02-060, will be investigated using chemical biology techniques in tandem with heme binding assays. The scientific impact of the successful completion of this project will result in a superior analog of MH02-060 that has the potential to be accepted into the Medicines for Malaria Venture's antimalarial clinical development pipeline. The completion of this proposal will result in my training in a diverse set of technical methodologies and knowledge of antimalarial drug development. Along with the training that I will receive from Dr. Riscoe and members of his lab, I will have additional training in: cell culture, in vitro antiplasmodial assays, and murine in vivo experiments by Dr. Jane Kelly and Dr. Yuexin Li; bioanalytical sample preparation and analysis from Dr. Andrea DeBarber; interpretation of proteomic data from Dr. Ashok Reddy; and optimization and use of the drug- like probes from Dr. Michael Cohen, all from OHSU. My position in Dr. Michael Riscoe's laboratory will provide me with institutional support from an exemplary department and access to a large group of diverse PI's and trainees to aid in my scientific growth and training. Development in these areas and amongst this institution will provide me with key skills and scientific development to pursue a successful career as an independent academic investigator.
