N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Abstract

African sleeping sickness or human African trypanosomiasis (HAT), caused by Trypanosoma brucei spp., is responsible for ~30,000 deaths each year. Available treatments for this neglected disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease, when the parasite has infected the central nervous system. Here, we report the validation of a molecular target and discovery of associated lead compounds with potential to address this unmet need. Inhibition of this target, T. brucei N-myristoyltransferase (TbNMT), leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have very promising pharmaceutical properties and represent an exciting opportunity to develop oral drugs to treat this devastating disease. Our studies validate TbNMT as a promising therapeutic target for HAT.

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…The cell surface of the bloodstream form has a dense coat of VSGs, which is replaced by an equally dense coat of procyclins pocket of the enzyme. The compounds identified are reported to have promising pharmaceutical properties and could be developed as oral drugs (176).…”

Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis

“…Several approaches have been taken to develop anti-HAT drugs, ranging from large compound library screening against the organisms in vitro (which is target-agnostic) to target-specific structure-based drug design (9,10). We have taken a hybrid approach to identify potential drugs for HAT.…”

Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense

“…Compound 8 was prepared because of the importance of N-myristoylation to the survival of T.b.brucei 35 in post-transitional modification, membrane targeting and the biological activity of many important proteins. Compound 20 the N-(4-amino-6-chloro-1,3,5-triazin-2-yl)-S-(2,4-dinitrophenyl) glutathione di-n-butyl ester derivative isolated instead of the desired compound, N-(2,4-diamino-1,3,5-triazin-2-yl)-S-(2,4-dinitrophenyl) glutathione di-n-butyl ester derivative, to act as a substrate of the P2 purine transporter.…”