Microtubules (MTs) constitute an essential component of the cytoskeleton in all eukaryotic cells and are involved in a number of important structural and regulatory functions, including the maintenance of cell shape, intracellular transport machinery, motility, as well as cell growth and division. MT-targeting drugs, which include MT- stabilizing and -destabilizing compounds, form a cornerstone of cancer chemotherapy; however, several studies suggest that such compounds may be also useful to treat other human diseases, including parasitic infections. From their ongoing studies to combat neurodegenerative diseases, the groups of Dr. Ballatore (UC San Diego) and Dr. Brunden (University of Pennsylvania) have synthesized and characterized a target-based library of >250 small molecules that are known to engage MTs and exhibit generally favorable drug-like properties, including brain penetration and oral bioavailability. This target-based library of non-commercially available compounds offers, therefore, an unique ?re-tooling? opportunity to develop new therapeutic leads for neuroparasitic diseases, such as Stage 2 Human African trypanosomiasis (HAT; Sleeping Sickness) and Primary Amebic Meningoencephalitis (PAM), which are caused by Trypanosoma brucei and Naegleria fowleri, respectively. Accordingly, our preliminary studies confirm that members of the triazolopyrimidine (TPD) and phenylpyrimidine (PPD) classes of MT-active compounds within our compound library kill N. fowleri and/or T. brucei with potencies equivalent to or exceeding those of the current drug standards. Representative compounds from this anti- parasitic subset have also undergone full pharmacokinetic (PK) analyses and in vitro safety pharmacology assessments suggesting the compounds are appropriate for in vivo anti-parasite efficacy studies. Thus, the goal of the R21 phase of this proposal is to: (a) complete the in vitro screening of available TPDs and PPDs; (b) determine the brain penetration of the most promising compounds; (c) conduct full PK and tolerability studies on selected molecules; and (d) conduct in vivo proof-of-concept experiments in animal models of HAT and PAM. Completion of the R21 studies will lead to the R33 phase, which will be focused on structure activity relationships, lead optimization, and mode of action studies.
We will investigate the efficacy and tolerability of a target-based library of brain-penetrant microtubule (MT)- stabilizing small molecules under development for treatment of neurodegenerative diseases as experimental compounds to treat Human African trypanosomiasis and primary amebic meningitis. After demonstrating proof-of- concept in animal models (R21 phase), the R33 phase will be will be focused on structure activity relationships, lead optimization and mode of action studies. Successful completion of the proposed research plan will lead to the identification of new drug candidates to treat parasitic infections of the central nervous system.