Like the natural hPF4 found in platelets, the most effective smHDPs tested targeted only infected red blood cells, attacking and destroying the parasite in exactly the same way, but with even greater potency and speed. "The smHDPs get into infected red cells and lyse or basically destroy the digestive vacuole or stomach of the parasite more rapidly than the hPF4 protein," Greenbaum notes. "The protein from platelets is about 25 times less potent, but the surprising thing is they act with the same mechanism. With ease, within seconds, they destroy the vacuole of the parasite."
Greenbaum's team settled on two compounds, PMX1207 and PMX207, for testing in mouse models of malaria. Both compounds significantly decreased parasitic growth and greatly improved survival rates, providing further confirmation of the potential of smHDPs as antimalarial agents. The work, Greenbaum says, shows that "we can translate a natural arm of the innate immune system in platelets to drug-like small molecules that we are honing to become potent, selective, potentially less toxic, and cheaper to make as an antimalarial."
Aside from their great effectiveness, smHDPs may have several other advantages over other antimalarial therapies. As Plasmodium inevitably adapts and becomes resistant to a particular drug therapy, the efficacy of that treatment decreases and survival rates drop. By mimicking the body's own natural defenses, the new HDP-centered approach could avoid that pitfall. "Certainly with malaria we've had a lot of problems in the last 20 years with resistance," Greenbaum explains. "One of the unique features of the synthetic HDPs
|Contact: Karen Kreeger|
University of Pennsylvania School of Medicine