Exploiting Diversity-Oriented Chemical Synthesis for Combating Chronic Parasitic Infection

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

PROJECT ABSTRACT Toxoplasma gondii is a widespread parasite of animals that causes opportunistic infections in humans. Although healthy humans control the infection, they are not able to completely eliminate the bradyzoite stage that reside in neurons and muscle cells. Hence, they remain chronically infected. Complications occur due to reactivation of chronic infections in immunocompromised patients. Complications also can arise from new infections during pregnancy when the parasite can cross the placental barrier and infect the developing fetus. It is estimated that ~ 2 billion people worldwide are chronically infected with T. gondii and hence at risk of reactivation should their immune functions decline. Existing chemotherapy for T. gondii is only effective at suppressing acute infection due to the tachyzoite stage but it is unable to eradicate the chronic bradyzoite stage. The goal of this project is to identify preclinical drug candidates that show potent inhibition of parasite growth including elimination of bradyzoites. Preclinical candidates will be identified based on efficacy against chronic toxoplasmosis in vivo and appropriate metabolism and safety profiles for advancement to the clinic. We will focus on the highly promising bicyclic pyrrolidine scaffold that targets phenylalanine tRNA synthetase (PheRS) to develop inhibitors that are both potent and selective. We will design, synthesize, and test new analogs to develop structure activity relationships for on-target activity. We will optimize potency, selectivity, brain penetration, bioavailability, metabolism and pharmacokinetic (PK) properties of lead compounds. Specific go no/go criteria for potency, selectivity and PK properties will be used to advance compounds to in vivo testing. Genetic and genomic approaches will be used to identify potential resistance mechanism, and to address the mechanisms of action of leads. We will employ quantitative assays for monitoring inhibition of bradyzoite growth in vitro, and animal models for monitoring the efficacy of lead compounds against reactivated toxoplasmosis in the brain. Successful achievement of these goals will deliver preclinical candidate(s) for future IND-enabling studies with the eventual goal of curing chronic toxoplasmosis.