Drug development of orally active anti-trypanosomiasis agents

Cleveland State University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): African trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease caused by Trypanosoma brucei. It threatens over 60 million people in 36 countries of sub-Saharan Africa where health systems are least effective, or even non-existent. There are no effective vaccines and satisfactory drugs for the treatment, and the development of new drugs for the disease is urgently needed. Trypanosome infections are now referred as 'most neglected diseases', and need more research efforts. Microtubules are very critical for the parasite cell division as well as flagellar motility. Cellulr division and locomotion are essential for the trypanosome survival. Therefore, tubulin inhibitors are expected to be promising anti-trypanosomiasis agents, since they interfere with microtubule dynamics and suppress both trypanosome cell division and cell movement. Tubulin is a well-recognized molecular target for anti- trypanosome drug development. On the other hand, tubulin is also a mature molecular target for anti- cancer drug development. Many tubulin inhibitors are first chemotherapy for cancer treatment in clinic. However, these tubulin inhibitors show very weak inhibitory activity to the trypanosome cell growth, because there are clear differences between trypanosome and mammalian tubulin. Currently, the task is to develop selective tubulin inhibitors only interfering with trypanosome cells. We identified several lead compounds selectively decreasing trypanosome cell viability from a tubulin inhibitor library initially develoed as anti-cancer agents. A structure-activity relationship (SAR) was summarized based on the anti-trypanosome cell activity of these compounds. The pharmacophore of the tubulin inhibitors enhancing the mammalian cell growth inhibition was different to the pharmacophore promoting the parasite growth inhibition. The results encourage us to expect that more selective and potent tubulin inhibitors against trypanosomiasis could be developed based on the preliminary SAR. To test the hypothesis, we will focus on three research aims listed below: 1) Optimize the lead compounds to generate more selective and potent tubulin inhibitors against trypanosomiasis. We will use medicinal chemistry approaches to design and synthesize new analogs, and test the compounds with trypanosome and human cell growth assays. More potent compounds with lesser toxicity will be identified. 2) Determine the tubulin polymerization inhibitory activity of the selected compounds. We will use tubulin proteins originally isolated fro mammalian and trypanosome cells to test the protein selectivity of the drug candidates. 3) Determine the in vivo anti-trypanosome activity and the bioavailability of the drug candidates. The oral activity and blood brain barrier passing ability of the drug candidates will be determined with animals.