Development of new drugs for Toxoplasma by advancing hits from the Global Health Chemical Diversity Library

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Toxoplasma gondii is a prolific eukaryotic parasite that is widely distributed throughout the world. Infection with T. gondii can cause severe and potentially fatal brain and eye disease, especially in immunocompromised individuals. Worldwide, T. gondii is also a leading infectious cause of blindness in otherwise healthy individuals. The current first-line therapy for T. gondii is a combination of the drugs pyrimethamine and sulfadiazine, but this regimen suffers from a number of shortcomings. These drugs must be taken for weeks to months, frequently cause toxic side effects, and are incapable of eradicating chronic infection. We need new medicines for T. gondii that are safer, better tolerated, more effective, and can be given for shorter durations. To this end, Dr. Alday and his colleagues have screened the 68,689 compounds in the Global Health Chemical Diversity Library (GHCDL) to find those that inhibit the growth of T. gondii. In doing so, 359 hit compounds were found that strongly inhibit the growth of this parasite. The potency of each of these has been measured and a subset of 73 highly potent and selective compounds selected for further study. All compounds in the GHCDL were chosen for their drug-like physicochemical properties that predict good absorption and distribution when taken orally. Therefore it seems reasonable to hypothesize that within the 359 compounds that strongly inhibit T. gondii growth are those that will be effective against toxoplasmosis when given orally and thus excellent starting points from which to develop new drugs. Dr. Alday's research will systematically evaluate this hypothesis in three parts. First, the potency of all 73 compounds will be verified. An initial study of the structure-activity relationships of the three most promising will be done. Secondly, Dr. Alday will determine the mechanism of action for the top 10 most promising compounds by creating resistant mutants and identifying relevant mutations using whole-genome sequencing. Finally, the effectiveness of the top 10 compounds will be tested in mouse models of infection. Dr. Alday is a physician-scientist at Oregon Health & Science University and the Portland VA Medical Center. Clinically, he is trained in internal medicine and infectious disease (ID), rotates on the inpatient ID consult service, and has an outpatient ID clinic. His PhD is in biochemistry, with a focus on the physical chemistry of protein-protein and protein-small molecule interactions. This unusual background gives him a strong background from which to pursue the work described in this CDA application. He has worked in the Portland VAMC Experimental Chemotherapy Lab with Dr. Michael Riscoe and Dr. Stone Doggett over the past three years, developing proficiency in the molecular and biochemical methods needed to evaluate drugs and their mechanism of action in protozoan parasites. The work proposed in this CDA will provide Dr. Alday with further training in drug design, evaluation of drug mechanisms, and in vivo efficacy studies he needs to become an independent VA investigator. As part of this training grant, he has assembled a team of senior scientists and physician-scientists with expertise in molecular parasitology and drug development. Collectively, they have mentored dozens of trainees towards independence. This panel will meet formally every six months to review Dr. Alday's progress. Additionally, this panel will provide input regarding experimental approaches, review manuscripts prior to publication, and give advise about career development. Dr. Alday will take graduate-level classes in pharmacokinetics and genome sequencing and present his work at scientific meetings. Prior to the end of this CDA, Dr. Alday will have identified promising lead compounds ready for advancement down the drug development pathway as well as new targets for future drug development efforts. Moving these leads forward will form the basis for VA Merit Review and NIH R01 grant applications that will establish him as an independent clinician-scientist devoted to caring for veterans afflicted by infectious diseases through service and research.