We continued to investigate the development of therapeutic agents against the invasion and pathogenicity of the malaria parasite in the heparin/heparan sulfate (H/HS) family of oligo-and polysaccharides and their mimetic sulfated xylan oligosaccharides. Malaria ranks in the top three deadliest diseases globally, with ~300 million clinical cases per year. 1-3% of the Plasmodium falciparum (Pf) parasites are more virulent causing severe and cerebral malaria and the death of ~2 million people; 90 % are young children. There is no preventive vaccine, and malarial parasites are increasingly resistant to anti-malarial drugs. Heparin inhibits the invasion of hepatocytes (the initial infection) by Pf parasites; may be involved in the invasion of RBCs; inhibits the rosetting and cytoadhesion of parasitized RBC (PfRBC) to normal RBC and the endothelium (a cause of severe malaria); and heparin was found to clear blockage of the microcirculation in a study of cerebral malaria in children. We prepared a library of H/HS-mimetic S-oligoS from a heparin-mimetic pharmaceutical (comprised of a mixture of chemically-sulfated oligoxylans which mimics numerous discrete biological actions of the heparin family). We developed a macro combinatorial strategy that examines whether a given heparin function, like anti-coagulation, would be separable and governed by structural specificity within the family, and whether the active component would likely lack anti-thrombin capacity as well (first applied to the anti-HIV-1 capacity of heparin/S-oligoS [HD001315-03-07]). These two characteristics are required indicators of usefulness in further drug development. Our anti-malaria findings, which showed that S-oligoS inhibited hepatocyte invasion and was governed by structural specificity, are consistent with the known molecular glycobiology of H/HS in its multifunctional modulation of anti-thrombin in the clotting cascade. We expanded our H/HS-mimetic library to generate appropriate S-oligoS to continue the anti-malarial studies. Experiments for further collaboration on inhibition of parasite invasion of hepatocytes and RBCs in vitro have been planned, as well as studies on the inhibition of the rosetting of PfRBC in vitro. Research on this project is limited by delays in staffing. Work is near complete on an enlarged heparin-mimetic library to examine the capacity to inhibit rosetting in vitro and identify a potential therapeutic agent for use against acute cerebral malaria. Additional experiments will elucidate the H/HS-mimetic ligands by a modified gel-shift analysis of heparin oligoS-protein binding, and the testing of possible protein ligands using fluorescent (monodansylated) receptors (library S-oligoS and/or heparin-oligoS).

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U.S. National Inst/Child Hlth/Human Dev
United States
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