| Parasitic diseases are a health threat of huge proportions, causing mortality and morbidity to hundreds of millions of people every year worldwide. Protozoan parasites, (for example Trypanosoma and Leishmania species) microscopic organisms capable of living within the cells of the host are one form. They have a variety of specialized defense mechanisms and life cycle strategies that allow them to defeat immune challenges and drug therapy. Many of these infections are chronic, allowing the parasites to keep a host infected for long periods of time and can be deadly in an immune compromised host.; Inorganic polyphosphates are linear polymers of orthophosphate residues linked by high-energy phosphoanhydride bonds found in every living organism. Numerous and varied biological functions are performed by polyphosphates. Among these functions are acting as a reservoir of energy and phosphate, a chelator of metals, a buffer against alkali, and in physiological adjustments to growth, development, stress, and deprivation. 31P NMR is a powerful technique to study the phosphate metabolism in cells. Spectra of trypanosomatids and show that polyphosphates are very abundant, especially in electron dense vacuoles present in them called acidocalcisomes.; Together with the recent discovery of several pyrophosphate-utilizing enzymes in these parasites, the spectra suggested that these polyphosphates could have an essential role in the survival of these parasites. Non-metabolizable analogs of the shortest polyphosphate, pyrophosphate, called bisphosphanates, are currently FDA approved for the treatment of bone resorption disorders like osteoporosis. Bisphosphonates selectively inhibited the proliferation of Trypanosoma cruzi in vitro and effected a radical cure of Leishmania mexicana in vivo. The mechanism of this growth inhibition is partly due to inhibition of enzymes of the mevalonate pathway, especially farnesyl pyrophosphate synthase. This gene from Trypanosoma cruzi was cloned and sequenced. Another set of compounds, aryloxyethyl thiocyanate derivatives, also thought to work on the sterol pathway, were also evaluated against T. cruzi and found to be potent growth inhibitors.; All together, this work represents a new approach to chemotherapy of important and difficult to treat diseases with a group of safe and well understood compounds not previously thought to be useful in infectious diseases. |
