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Abstract:

The progresses made in the field of drug design to combat tropical protozoan parasitic diseases, such as Chagas' disease, leishmaniasis, and sleeping sickness are discussed. This article is focused on different approaches based on unique aspects of parasites biochemistry and physiology, selecting the more promising molecular targets for drug design. In spite of the enormous amount of work on the above features, the chemotherapy for all of these diseases remains unsolved. It is based on old and fairly not specific drugs associated, in several cases, with long-term treatments and severe side effects. Drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. In this review article, a thorough analysis of selected molecular targets, mainly those that are significantly different compared with the mammalian host or, even, are not present in mammals would be described in terms of their potencial usefulness for drug design. Therefore, this article covers rational approaches to the chemotherapeutic control of these parasitic infections, such as the progresses in the search for novel metabolic pathways in parasites that may be essential for parasites survival but with no counterpart in the host. Ergosterol biosynthesis is a very interesting example. There are many enzymes involved in this biosynthetic pathway such us squalene synthase, farnesylpyrophosphate synthase, and other enzymes that are able to deplete endogenous sterols will be treated in this article. The enzymes involved in trypanothione biosynthesis, glutathionyl spermidine synthetase and trypanothione synthetase do not have an equivalent in mammals, and therefore it can be predicted low toxicity for compounds that are able to produce highly selective inhibition. Trypanothione reductase (TR), glyceraldehyde-3-phosphate dehydrogenase, dihydrofolate reductase, prenyltransferases, ornithine decarboxylase, etc, will be thoroughly analyzed. The design of specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts will be presented. The recent advances in the biochemistry of pathogenic parasites including the discovery of novel organelles will be discussed. © 2006 Bentham Science Publishers Ltd.

Registro:

Documento: Artículo
Título:Progresses in the field of drug design to combat tropical protozoan parasitic diseases
Autor:García Liñares, G.E.; Ravaschino, E.L.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, C1428EHA Buenos Aires, Argentina
Palabras clave:2 (2,4 difluorophenyl) 1 [3 [2 [4 (2,2,3,3 tetrafluoropropoxy)phenyl]vinyl] 1,2,4 triazol 1 yl] 3 (1,2,4 triazol 1 yl) 2 propanol; amphotericin B; antiprotozoal agent; benznidazole; crystal violet; dihydrofolate reductase; dimethylallyltransferase; eflornithine; ergosterol; geranyltransferase; glyceraldehyde 3 phosphate dehydrogenase; ici 195 739; ketoconazole; meglumine antimonate; melarsoprol; miltefosine; nifurtimox; ornithine decarboxylase; paromomycin; pentamidine; sitamaquine; spermidine derivative; squalene synthase; suramin; terbinafine; thiocyanic acid derivative; triazole derivative; trypanothione; trypanothione reductase; unclassified drug; unindexed drug; antiprotozoal agent; African trypanosomiasis; anorexia; antibiotic sensitivity; antiprotozoal activity; biosynthesis; Chagas disease; disease course; disease severity; disease transmission; drug design; drug mechanism; drug research; drug specificity; drug structure; drug targeting; gene targeting; human; infection control; leishmaniasis; long term care; nonhuman; parasite survival; peripheral neuropathy; review; skin allergy; structure analysis; teratogenicity; Toxoplasma gondii; Trypanosoma brucei; Trypanosoma cruzi; vomiting; Chagas disease; drug design; leishmaniasis; trypanosomiasis; Antiprotozoal Agents; Chagas Disease; Drug Design; Humans; Leishmaniasis; Trypanosomiasis
Año:2006
Volumen:13
Número:3
Página de inicio:335
Página de fin:360
DOI: http://dx.doi.org/10.2174/092986706775476043
Título revista:Current Medicinal Chemistry
Título revista abreviado:Curr. Med. Chem.
ISSN:09298673
CODEN:CMCHE
CAS:2 (2,4 difluorophenyl) 1 [3 [2 [4 (2,2,3,3 tetrafluoropropoxy)phenyl]vinyl] 1,2,4 triazol 1 yl] 3 (1,2,4 triazol 1 yl) 2 propanol, 103961-78-0, 141113-28-2; amphotericin B, 1397-89-3, 30652-87-0; benznidazole, 22994-85-0; crystal violet, 467-63-0, 548-62-9; dihydrofolate reductase, 9002-03-3; dimethylallyltransferase, 9032-79-5; eflornithine, 67037-37-0, 70052-12-9; ergosterol, 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4; geranyltransferase, 37277-79-5, 50812-36-7; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; ketoconazole, 65277-42-1; meglumine antimonate, 133-51-7; melarsoprol, 494-79-1; miltefosine, 58066-85-6; nifurtimox, 23256-30-6; ornithine decarboxylase, 9024-60-6; paromomycin, 11035-13-5, 1263-89-4, 1390-73-4, 51795-47-2, 54597-56-7, 7542-37-2, 84420-34-8; pentamidine, 100-33-4; sitamaquine, 5330-29-0, 57695-04-2; squalene synthase, 9077-14-9; suramin, 129-46-4, 145-63-1; terbinafine, 91161-71-6; trypanothione reductase, 102210-35-5; trypanothione, 96304-42-6; Antiprotozoal Agents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09298673_v13_n3_p335_GarciaLinares

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Citas:

---------- APA ----------
García Liñares, G.E., Ravaschino, E.L. & Rodriguez, J.B. (2006) . Progresses in the field of drug design to combat tropical protozoan parasitic diseases. Current Medicinal Chemistry, 13(3), 335-360.
http://dx.doi.org/10.2174/092986706775476043
---------- CHICAGO ----------
García Liñares, G.E., Ravaschino, E.L., Rodriguez, J.B. "Progresses in the field of drug design to combat tropical protozoan parasitic diseases" . Current Medicinal Chemistry 13, no. 3 (2006) : 335-360.
http://dx.doi.org/10.2174/092986706775476043
---------- MLA ----------
García Liñares, G.E., Ravaschino, E.L., Rodriguez, J.B. "Progresses in the field of drug design to combat tropical protozoan parasitic diseases" . Current Medicinal Chemistry, vol. 13, no. 3, 2006, pp. 335-360.
http://dx.doi.org/10.2174/092986706775476043
---------- VANCOUVER ----------
García Liñares, G.E., Ravaschino, E.L., Rodriguez, J.B. Progresses in the field of drug design to combat tropical protozoan parasitic diseases. Curr. Med. Chem. 2006;13(3):335-360.
http://dx.doi.org/10.2174/092986706775476043