| الوصف: |
Despite intense world-wide effort, malaria is still a major cause of morbidity and mortality, especially in third world countries. Malaria is the result of an intracellular parasite, with Plasmodium falciparum being the most lethal species. The emergence of resistance to current anti-malarial therapies in Plasmodium is spreading, but conceivably can be circumvented by targeting processes within the host red blood cell (RBC) required for pathogenesis. For example, a crucial step in the parasite’s lifecycle is weakening of the host RBC’s membrane via modification of host membrane proteins, including the integral RBC membrane protein band 3. This membrane weakening eventually leads to the cell’s lysis, releasing parasites to infect additional RBCs. The weakening of the RBC membrane represents an intriguing target as the band 3 protein responsible for the weakening is modified via tyrosine phosphorylation and the parasite encodes no classical tyrosine kinases in its genome. Over 75% of band 3 is lost by the end of egress, which is critical since the band 3-ankyrin interaction constitutes the major connection linking the cell membrane to the cytoskeleton. Curiously, phosphorylation of band 3 tyrosines by RBC Syk kinase also induces release of band 3 from the cytoskeleton, leading to membrane destabilization and fragmentation. Since tyrosine phosphorylation of band 3 is prominent during the later stages of intra-erythrocytic parasite development, we evaluated a variety of tyrosine kinase inhibitors (TKIs) to assess their abilities to block parasite egress by inhibiting the tyrosine phosphorylation of band 3. In healthy RBC treated with orthovanadate (OV) to induce band 3 tyrosine phosphorylation, Syk inhibitors were the most effective inhibitors of this phosphorylation followed by inhibitors of Src-family kinases. Results reinforce the prominent role of Syk in this process and illustrate a previously unidentified role of tyrosine kinases Hck, Fgr, and c-Src. With these results in mind, P. falciparum cultures were ... |