Current Topics in Medicinal Chemistry - Volume 2, Issue 5, 2002

Parasite infections affect billions of humans world-wide, yet the current drugs available for the treatment of many parasitic diseases are either inadequate, or compromised by the development of resistance. Validation of a drug target is an important step in the development of new drugs. Target validation encompasses verifying that a target is primarily responsible for the therapeutic activity of a proven drug, or demonstrating the essential nature of a putative drug target in a parasite, and the capacity for selective inhibition of that target in vivo. Selective toxicity may be achieved by taking advantage of unique parasite biology or biochemistry, or by utilizing differences in metabolism or import. The essential nature of a target may be demonstrated by the correlation of the chemical or genetic reduction of target activity with the loss of parasite growth or virulence. Rescue experiments may demonstrate the single nature of a target. Ultimately, a target must be validated in vivo.

Glycolysis is considered as a promising target for new drugs against parasitic trypanosomatid protozoa, because this pathway plays an essential role in their ATP supply. Trypanosomatid glycolysis is unique in that it is compartmentalised, and many of its enzymes display specific structural and kinetic features. Structure- and catalytic mechanism-based approaches are applied to design compounds that inhibit the glycolytic enzymes of the parasites without affecting the corresponding proteins of the human host. For some trypanosomatid enzymes, potent and selective inhibitors have already been developed that affect only the growth of cultured trypanosomatids, and not mammalian cells. Examples are developed concerning all enzymes in the hexoses part with also others concerning glyceraldehyde-phosphate dehydrogenase and pyruvate-kinase for the trioses part.Concerning cysteine protease inhibitor development, a great number of irreversible alkylating agents have shown their efficacy towards the active site cysteine of parasite proteases. This includes fluoromethylketones, epoxides, diazomethylketones, vinylsulfones to mention a few. These functional groups are activated electrophiles that react with the nucleophilic cysteine of the active site and are generally quite selective for cysteine versus serine. They are thought to be also reactive to numerous other nucleophiles in the body, especially other thiols. This potentially hampering property seems not to be detrimental for two reasons: first a recent report has shown that cysteine protease inhibitors containing a vinylsulfone electrophile are unreactive towards thiols such as glutathione and can be considered to be inert in the absence of catalytic machinery. Secondly, irreversible inhibitors are shown to be less toxic than presumed in the parasite treatment, owing to some bioselectivity displayed by the parasite itself.

Millions of people worldwide are infected by some kind of parasite and millions are in risk of contracting infection. In addition, it is now accepted that parasites are rapidly developing resistance to drugs that a few years ago were effective. This gloom picture underscores the urgent need to develop new drugs against parasitic diseases. Fortunately, the important technological advances that have been made in the past years will, in principle, facilitate the discovery of new and effective agents against parasitic diseases. In many of the approaches for drug design the basic premise is the identification of a macromolecule that is central to the life of the parasite. Because the life of all living organisms depends on multiple protein-protein interactions and the function of oligomeric proteins, it is worthwhile to explore if protein interfaces could be exploited for drug design. Here we review some of the work that has been done in this direction, and attempt to call attention to the richness of protein-protein interfaces for the design of agents that could lead to the development of drugs against parasitic diseases.

Diseases caused by pathogenic trypanosomatids cause great suffering throughout the developing world. New drugs for these diseases are urgently needed. Recent technological advances have permitted the identification and validation of numerous drug targets in these organisms. However, efforts to develop inhibitors of these targets, that may then be taken forward for development into new drugs, have been comparatively scarce. In this review we discuss the design, synthesis and evaluation of inhibitors of two drug targets in trypanosomatids, 6- phosphogluconate dehydrogenase, the third enzyme of the pentose phosphate pathway, and dihydrofolate reductase, a key enzyme involved in DNA synthesis. Enzyme inhibitors can only be useful as drugs if they can enter cells and bind to their targets. Therefore we also discuss approaches to designing molecules that can specifically cross the plasma membrane of African trypanosomes via unusual nutrient transporters.

Development of drug resistance by Plasmodium falciparum and insecticide resistance by the mosquito has lead to the resurgence of the most virulent forms of malaria. This review aims to provide a general perspective on drug design for P. falciparum malaria. Though numerous targets have been identified, new clinically useful target-specific inhibitors remain a distant prospect. This review focuses on pathways and enzymes for which some structural information and detailed biochemistry along with specificity of inhibitor action is available. Aspects of the parasite glycolytic pathway, nucleotide metabolism, proteases, redox metabolism and organelle function have been used to highlight possible targets and molecules that could inhibit their function.