Protein structure-based design of anti-protozoal drugs

Journal of the Brazilian Chemical Society

Choe, Jungwoo¹  Suresh, Stephen¹  Hol, Wim G. J.¹  Bressi, Jerome C.¹  Buckner, Frederick S.¹  University of Washington, Seattle, USA¹  Biomolecular Structure Center¹  Christian de Duve Institute of Cellular Pathology, Brussels, Belgium¹  Verlinde, Christophe L. M. J.¹  Van Voorhis, Wesley C.¹  Gelb, Michael H.¹  Michels, Paul A. M.¹ 

关键词: drug design;    Chagas' disease;    leishmaniasis;    malaria;    African trypanosomiasis;    GAPDH;   

DOI  :  10.1590/S0103-50532002000600018

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Tropical protozoal diseases: a challenge The World Health Report 2000 lists 55 million deaths in 1999 due to all causes. Tragically, specific protozoal diseases occupy a prominent place in this list. 1,086,000 people died from malaria, 66,000 from African trypanosomiasis, 21,000 from Chagas' disease, 14,000 from schistosomiasis, and 57,000 from leishmaniasis.1 Premature death captures only part of the picture. These sobering statistics are further supplemented with burden of disease data expressed in DALYs, disability-adjusted life years robbed by disease: 45 million by malaria, 2 million by trypanosomiasis; 0.7 million by Chagas' disease; 2 million by schistosomiasis; and 2 million by leishmaniasis.1 In turn, a large burden of disease impedes economical growth and prosperity, further compounding the misery.2 At first sight, little change in this sad situation is to be expected. The geographical distribution of these diseases is mainly centered about the tropics, where the climate favors persistence of the vectors for transmission. Vector control is possible, eradication probably not.3 Vaccine development has not been successful thus far, mainly because parasites are experts at evading or dysregulating the human immune system. For example, trypanosomes can switch among 1000 genes encoding for their surface glycoprotein, and malaria-infected erythrocytes adhere to the antigen-presenting dendritic cells, thereby preventing their maturation and the proper mounting of an immune response.4,5 Chemotherapy to fight the mentioned diseases exists, but is plagued by high toxicity and increasing resistance. For example, melarsoprol, the only drug that can cure late-stage T.brucei rhodesiense trypanosomiasis, kills 5 % of the patients.6 Adding insult to injury, pharmaceutical companies steer away from vaccine and drug development to fight tropical diseases because such programs do not fit in their profit-driven business model. Yet, many new opportunities are on the horizon thanks to fundamental parasitology research, parasite genome sequencing efforts, advances in structural biology methods, the ability to generate many molecules by combinatorial chemistry, and the integration of the latter into structure-based drug design methods. New opportunities for chemotherapy The current list of validated targets for new drugs against trypanosomatids includes glycolytic enzymes, trypanothione reductase, cathepsin L-like proteases, various kinases, and protein farnesyl tranferase.7 New targets in Plasmodium are protein prenylation, hemoglobin degradation in the food vacuole, mitochondrion electron transport, and apicoplast metabolism.8 The discovery of the apicoplast, a chloroplast-like organelle, was completely unexpected and due to genomics. Yet, more surprises are to be expected. The malaria genome sequencing effort is expected to be completed by mid 2002.9 Meanwhile, the sequencing of the genomes from Trypanosoma brucei, Trypanosoma cruzi, Schistosoma mansoni, and Leishmania major are underway.10 Also, 2001 saw the birth of an academic consortium, named SGPP (= Structural Genomics for Pathogenic Protozoa; see: www.sgpp.org). This consortium plans to determine the three-dimensional structures of several hundreds of proteins from T.brucei, T. cruzi, various Leishmania sub-species, and Plasmodium falciparum. Hence, medicinal chemists will have a quickly expanding list of opportunities to design and synthesize the anti-protozoal drugs of the future.    Results and Discussion Trypanosomal glycolysis: a

【 授权许可】

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