Optimization of pharmaceutical properties of a lead compound targeting human African trypanosomiasis by nano formulations


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Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei.  HAT is present in 36 countries in sub-Saharan Africa, has 70 million people at risk, and causes 10,000 new cases each year.  Current drug therapies need improvement in efficacy, reduced toxicity, and bioavailability.  As a result, new research is being conducted in the pursuit of small molecule chemotherapeutics that target HAT.

Using a drug target repurposing approach, we discovered that lapatinib, a human epidermal growth factor receptor (EGFR) inhibitor, exhibited modest potency with an EC50 of 1.54 micromolar against T. brucei.  Through structure-activity relationship (SAR) studies, a lead compound, NEU-617, was synthesized and shown to have an EC50 of 42 nM as well as excellent selectivity over human cells.  Despite these promising results, NEU-617 has poor physiochemical properties for targeting the blood-brain barrier (BBB): high molecular weight (541), high lipophilicity (clogP = 7.1) and high binding to plasma proteins (>99%).  Indeed, we do not see significant levels of the drug in the central nervous system, which is critical for HAT therapeutics.

Nanoformulations have been shown to avoid first pass metabolism, generating prolonged exposures to a drug.  Also, nanoformulations rich in fatty acids can aid in BBB penetration.  We describe here our ongoing studies of applying nanoformulation technology to NEU-617 to improve its applicability as a potential HAT therapeutic.