We have focused on antimitotic peptides, often of marine origin, because these are among the most potent anti-MT agents known, they have been synthesized and analogs are available, and because they induce the MT subunits to assume unusual and characteristic ring shapes. We are studying the structural and dynamic properties of these ring polymers by analytical ultracentrifugation, cryoelectron microscopy, fluorescence correlation spectroscopy, and protease mapping. The high stability and uniformity of these rings that our studies revealed have led us to attempt crystallization of these polymers to achieve atomic resolution of their structure. We are also examining the effects on microtubule polymerization of synthetic analogs of thalidomide and combretastatin A. We have also demonstrated the role of posttranslational modifications by deacetylases, and the effects of proteasome inhibitors on microtubule stability.? We have identified a number of new modified peptides derived from the natural peptide tubulysin. Thes new peptides show a range of antimicrotubule activity in assays with purified proteins as well as in cells. In addition we have examined a new """"""""second generation"""""""" of microtubule stabilizers, focusing on the natural compound peloruside. We have also shown that an old chemotherapy agent, a nitrosourea, may affect microtubule stability indirectly by altering the activity of the protein stathmin. This results in reduced migration and invasion by malignant glioma cells.? We are seeking to identify small molecules that do not bind well with mammalian tubulin but do bind to parasite tubulin. The tubulin molecule is quite conserved evolutionarily, but differences do exist, and several molecules are known that can target, for example, yeast rather than mammalian tubulin or vice-versa. We are looking for molecules that will target Leishmania, the infectious cause of an important group of human diseases. We have identified several small molecules that show promise as selective agents, binding to Leishmania tubulin preferentially over mammalian tubulin, and preventing parasite multiplication inside human macrophage cells.
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