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American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The rapid development by malaria parasites of resistance to almost all the chemotherapeutic agents so far used for their control means that constant efforts to develop new drugs are necessary. In this review, we propose that the exploration of protein-protein interactions as a new strategy to identify antimalarial drug targets is an attractive and a promising area of research. Nevertheless, one of the most important criteria is that the targeted gene should encode an essential protein within a complex that is able to affect parasite survival. Recently, our research on the biology of Plasmodium falciparum allowed us to identify the interaction of Protein Phosphatase type 1 and actin with two essential partners, PfLRR1 and PfLRR7 respectively, both of which belong to the Leucine Rich Repeat (LRR) protein family. LRR-containing proteins are composed of several consensus LRR motifs LXLXXNXL (where X is any amino acid) that provide sites for the assembly of protein interactions. The LRR combines structural versatility, adaptability and more importantly a high degree of interaction specificity. In addition, it has been shown that a single mutation in a particular LRR motif abolishes the protein-protein interaction and contributes to the expression of severe pathology in humans. This clearly infers that blocking the interaction related to 'hot spots' of LRR motifs can be considered as good targets to block parasite growth and development. Thus, the inhibition of protein-protein interactions by peptides, peptidomimetics or small-molecule inhibitors that interfere with binding domains can contribute to defining new potential drug targets.

Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins expressed from various stages of parasite development. Proteomic methods can be applied to study sub-cellular localization, cell function, organelle composition, changes in protein expression patterns in response to drug exposure, drug-protein binding and validation of data from genomic annotation and transcript expression studies. Recent high-throughput proteomic approaches have provided a wealth of protein expression data on P. falciparum, while smaller-scale studies examining specific drug-related hypotheses are also appearing. Of particular interest is the study of mechanisms of action and resistance of drugs such as the quinolines, whose targets currently may not be predictable from genomic data. Coupling the Plasmodium sequence data with bioinformatics, proteomics and RNA transcript expression profiling opens unprecedented opportunities for exploring new malaria control strategies. This review will focus on pharmacological research in malaria and other intracellular parasites using proteomic techniques, emphasizing resources and strategies available for Plasmodium.

Cysteine proteases represent a broad class of proteolytic enzymes widely distributed among living organisms. Although well known as typical lysosomal enzymes, cysteine proteases are actually recognized as multi-function enzymes, being involved in antigen processing and presentation, in membrane-bound protein cleavage, as well as in degradation of the cellular matrix and in processes of tissue remodeling. Very recently, it has been shown that the NO(-donor)-mediated chemical modification of the Cys catalytic residue of cysteine proteases, including Coxsackievirus and Rhinovirus cysteine proteases, cruzain, Leishmania infantum cysteine protease, falcipain, papain, as well as mammalian caspases, cathepsins and calpain, blocks the enzyme activity in vitro and in vivo. Here, inhibition of representative cysteine proteases by NO(-donors) is reviewed.

The protozoan parasites, Trypanosoma brucei and T. cruzi, that cause sleeping sickness in sub-Saharan Africa and Chagas' Disease in Latin America, respectively, exert significant morbidity and mortality in man. Combinations of toxicity and differential efficacy of current drugs provide an urgent need to develop novel, cheap and effective chemotherapies. Research over the last decade with cultured trypanosomes and mice experimentally infected with these parasites has demonstrated that trypanosome cysteine proteinases are valid targets for the rational design of new drugs. In particular, potent peptidyl and peptidomimetic inhibitors of brucipain (a.k.a. trypanopain-Tb) and cruzain (a.k.a. cruzipain), the respective cysteine proteinases of T. brucei and T. cruzi, have proved trypanocidal. Efforts are ongoing to develop more specific non-toxic inhibitors of various chemistries with improved biological half-lives and biovailability characteristics. Here, the biochemical and biological properties together with the history, current status and perceived directions on the development of specific inhibitors of trypanosome cysteine proteinases will be reviewed.