multiple copies of a peptide envelope with four arms around lipids to create particles that mimic the behavior of HDL, the "good" cholesterol.
Y.Zhao et al., J. Am. Chem. Soc., 135 (2013)
A new drug candidate designed to mimic "good" cholesterol from the body shows a striking ability in mice with cholesterol levels in the blood and dissolve obstruction of the arteries plates. In addition, the compound functions when administered orally rather than by injection. If the results are valid in man-a big if, given past failures to transfer promising treatments mouse it could provide a new way to fight against atherosclerosis, the biggest killer in developed countries.
Although doctors have effective cholesterol-lowering agents such as statins, to them, there is room for improvement. Statin drugs have significant side effects in some people and may not reduce cholesterol enough in others. "There are still a lot of heart disease there, even among people taking statins," said Godfrey Getz, an experimental pathologist at the University of Chicago in Illinois.
For this reason, researchers around the world are looking for new drugs that affect cholesterol levels in one of two ways. the first was to reduce low-density lipoprotein (LDL), commonly known as bad cholesterol, which was associated with a higher risk of heart disease. This is the objective of statins, which block an enzyme involved in cholesterol production. the second strategy is to increase the levels of good cholesterol or high density lipoprotein ( HDL), which seems to improve heart health in people who have a lot of it. But the production of HDL raising drugs that prevent heart disease has been difficult. in the body, a large protein called apolipoprotein AI (apoA-I ) wraps around fatty lipid molecules to create HDL particles sop LDL and transport to the liver where it is eliminated. Thus, for decades researchers have designed and test small protein fragments called peptides to see if they could mimic the behavior of apoA-I. Such a peptide, known by the name 4F, did not reduce the serum cholesterol levels, but it narrows arterial plaques in mice, rabbits and monkeys. And in an early clinical trial by researchers from Bruin Pharma Inc. in Beverly Hills, California, which was designed only to measure its safety in people, 4F does not seem to show a beneficial effect.
M. Reza Ghadiri, a chemist at the Scripps Research Institute in San Diego, California, and his colleagues took a slightly different angle, creating a peptide that mimics another part of the apoA-I protein that is 4F. The first in vitro studies have suggested that particles of HDL-like peptide formed and sopped up LDL, an encouraging result that prompted them to push it further. Ghadiri and his Scripps colleagues tested their compound in mice that develop the artery clogging plaques when fed a high-fat diet of Western style. One group of animals received the peptide intravenously. For another group, the researchers simply added the compound to water animals, a strategy they considered unlikely to work, because the intestine contains high quantities of proteases designed to cut proteins apart . To their surprise, in both groups, serum cholesterol fell by 40% compared to previous levels within 2 weeks to start taking the drug. And 10 weeks, the number of lesions of the artery-clogging has been halved, the team reports in the October issue of Journal of Lipid Research . What remains puzzling, however, is that Ghadiri and his colleagues detect peptides in their blood of their test animal. Ghadiri said this suggests that the new peptide can work in removing cholesterol precursors in the gut before they enter the blood.
"It is a very interesting result," said Getz. But he warned that the work has only been tested in animals, and many therapies, including the closely related 4F peptide fail to pass to humans. However, Getz noted that some early promising results with this peptide and other mimics ApoA-I offers hope that researchers may soon come up with new drugs to dissolve artery blockage plates before they can cause their havoc.
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