Chemo-Immunotherapeutic Anti-Malarials Targeting Isoprenoid Biosynthesis.

ABSTRACT: We synthesized 30 lipophilic bisphosphonates and tested them in malaria parasite killing (targeting parasite geranylgeranyl diphosphate synthase, GGPPS) as well in human γδ T cell activation (targeting human farnesyl diphosphate synthase, FPPS). Similar patterns of activity were seen in inhibiting human FPPS and Plasmodium GGPPS, with short to medium chain-length species having most activity. In cells, shorter chain-length species had low activity, due to poor membrane permeability, and longer chain length species were poor enzyme inhibitors. Optimal activity was thus seen with ~C₁₀ side-chains, which have the best combination of enzyme inhibition and cell penetration. We also solved the crystal structure of one potent inhibitor, bound to FPPS. The results are of interest

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC3630516 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature