Trypanosoma brucei inhibitor

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

Glycolysis provides the main source of ATP in Trypanosoma brucei, E histolytica, and G lamblia, which possess pyruvate kinase as well as a pyruvate phosphate dikinase for converting phosphoenolpyruvate (PEP) to pyruvate and generating ATP. Pyruvate phosphate dikinase is not a homolog of pyruvate kinase but is closely related to PEP synthase from bacteria. The enzyme catalyzes conversion of PEP to pyruvate accompanied by the synthesis of ATP from AMP and pyrophosphate. Genes encoding the enzyme have been isolated from E histolytica and G lamblia and have demonstrated considerable structural divergences. No specific inhibitor of this enzyme has yet been identified. 

If the experimental tests confirm some compounds as inhibitors at the protein level, it is generally necessary to modify these inhibitors to optimize important pharmacokinetic properties, such as membrane permeability, drug-likeness, or cytotoxicity. For example, the five low-micromolar T REL1 inhibitors (VI, V3, V4, SI, and S5 in Fig. 3) identified by Amaro et al. (31) were effective against 7I REL1 in in vitro protein-level assays but were found to be ineffective against whole-cell Trypanosoma brucei, likely because of their low membrane permeability. 

Amaro RE, Schnaufer A, Interthal H et al (2008) Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei. Proc Natl Acad Sci USA 105 17278-17283. doi 10.1073/pnas.0805820105... 

Durrant JD, Hall L, Swiff RV et al (2010) Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. PLoS Negl Trop Dis 4 e803. doi 10.1371/ journal.pntd.0000803... 

Naphthalene-based RNA editing inhibitor blocks RNA editing activities and editosome assembly in Trypanosoma brucei. J Biol Chem 286 14178-14189. doi 10.1074/jbc. 

M. Engstler, R. Schauer, M. A. Ferrero-Garcia, A. J. Parodi, T. Storz-Eckerlin, A. Vasella, C. Witzig, and X. Zhu, N-(4-Nitrophenyl)oxamic Acid and Related N-Acylanilines Are Non-competitive Inhibitors of vibrio cholerae sialidase but do not inhibit trypanosoma cruzi or trypanosoma brucei trans-sialidases, Helv. Chim. Acta., 77 (1994) 1166-1174. 

Compounds of type 135 and 141 have been synthesised as inhibitors of PFT, an enzyme that catalyses the transfer of the farnesyl group from farne-syl pyrophosphate to the cysteine SH in the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The parent compound 140 (Ar = (2,4,6-trimethylphenyl) is the most active (ED50 10 xM) [44, 45]. This class of compounds has been tested also on mammalian PFTase and some of them showed inhibitory activity. In particular, none of the dihydro derivatives affects the enzyme in a concentration-dependent manner. 

Byers, T. L., Bush, T. L., McCann, P. P. and Bitonti, A. J. (1991) Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. Biochem. J. 274 527 533. 

Bitonti, A. J., Byers, T. L., Bush, P. J. et al. (1990) Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionione. Antimicrob. Agents Chemother. 34, 1485-1490. 

Bacchi, C. J., Nathan, H. C., Clarkson, A. B., Bienen E. J., Bitonti, A. J. and McCann P. O. (1987) Effects of the ornithine decarboxylase inhibitors DL-alpha-dilluoromethylornithine and alpha-monofluroromethyldehydroornithine methyl ester alone in combination with serum against Trypanosoma brucei brucei central nervous system models. Am. J. Trop. Med. Hyg. 36 46-52. 

Das A Gale Jr M, Carter V et al. The protein phosphatase inhibitor okadaic acid induces defects in cytokinesis and organellar genome segr tion in Trypanosoma brucei. J Cell Sci 1994 107(Pt 12) 3477-83. 

Bangs JD, Ransom DA, Nimick M et al. In vitro cytocidal effects on Trypanosoma brucei and inhibition of Leishmania major GP63 by peptidomimetic metalloprotease inhibitors. Mol Biochem Parasitol 2001 114 111-117. 

Bero, J., Beaufay, C., Hannaert, V., Herent, M. E., Michels, P. A.. Quetin-Leclercq, J. 2013. Antitrypanosomal compounds from the essential oil and extracts of Keetia leucantha leaves with inhibitor activity on Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase. 20(3-4) 270-274. 

African sleeping sickness, another widespread epidemic, is caused by Trypanosoma brucei, which is transmitted by flies. Ornithine decarboxylase (ODC), a key enzyme in the pathway for the synthesis of polyamines, is a target enzyme for drug development. Alpha-diflnoromethyl ornithine, an irreversible inhibitor of ODC, has been developed for the treatment of sleeping sickness (93). 

Samson, I., Kerremans, L., Rozenski, J., Samyn, B., Van Beeumen, J., Van Aerschot A. and Herdewijn, R, Identification of a peptide inhibitor against glycosomal phospho-glycerate kinase of Trypanosoma brucei by a synthetic peptide library approach, Bioorg. Med. Chem. Lett., 3 (1995) 257-265. 

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