July 18, 2006
La Jolla, CA – A natural chemical that has been ignored by researchers largely because of the runaway success of the blockbuster statin drugs may in fact yield a rare twofer: a prime target for novel cholesterol-lowering drugs and the blueprint for a new generation of antibiotics that can take down Streptococcus pneumonia and Staphylococcus aureus.
As it turns out, whether you are a human who synthesizes cholesterol, a plant making carotenoids or a bacterium just striving to survive, you need the mevalonic acid pathway. This biochemical pathway is essential for synthesizing cholesterol, steroid hormones and other essential cellular compounds.
Howard Hughes Medical Institute investigator Joseph Noel, Ph.D., and his colleagues at the Salk Institute for Biological Studies have spent the past two years learning how a chemical compound can shut down this crucial pathway. Now his group is using an approach that Noel calls “molecular dentistry,” to custom design chemicals with unique shapes that can switch off a crucial enzyme in the mevalonic acid pathway. The Salk researchers published their findings online the week of July 17, 2006, in the early edition of the Proceedings of the National Academy of Sciences.
Many organisms — including people, plants, and some types of bacteria — use the same set of enzymes to produce compounds known as isoprenoids. These chemicals serve as the starting material for a host of biological compounds, such as vitamin D, various hormones, and cholesterol. Interfering with the mevalonic acid metabolic pathway – the chemical factory that churns out isoprenoids – is the strategy behind the powerful effects of some top-selling, cholesterol-lowering drugs. These drugs, collectively known as statins (Lipitor, Mevacor, and Zocor are examples), prevent cholesterol formation by blocking the activity of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMGR).
Noel and his colleagues were interested in an enzyme that works with HMGR in the mevalonic acid pathway. They sought to understand how this enzyme, known as 3-hydroxy-3-methylglutaryl CoA synthase, or HMGS, interacts with F-244, a powerful HMGS inhibitor produced by certain species of fungi.
“HMGS could be an important alternative target for cholesterol-lowering drugs, but it has been little studied because the statin drugs have been so well developed,” said Noel, a professor in the Jack H. Skirball Center for Chemical Biology. “Although the statins are effective, it has been learned over the last few years that they have side effects sometimes caused by their interactions with other targets in the body besides HMGR,” he said. Drugs that target HMGS have the potential to avoid these side effects, which include abnormal liver function and muscle damage.
Postdoctoral fellow and first author Florence Pojer, Ph.D., Noel, and their colleagues explored the interaction between HMGS and F-244 using protein x-ray crystallography. The researchers settled on the version of HMGS found in the plant Brassica juncea, a species of mustard plant, because it more closely resembles human HMGS than other forms that had been studied in the past.
The structural analysis of HMGS bound to F-244 revealed important insights into the interaction between HMGS and the natural product that will guide drug development, said Noel. “Trying to improve the selectivity and potency of these compounds using synthetic chemistry, we think of the F-244 molecule as composed of two distinct components,” he said. “We refer to the reactive piece that switches HMGS off as the ‘warhead,’ because it reacts with the HMGS enzyme’s catalytic machinery to block its action. This warhead has to remain invariant because the HMGS catalytic machinery is the same from species to species.”
However, their data revealed that the other component of F-244, a tail-like structure that they call the ‘guidance system,’ can be readily modified using rational drug design to chemically mold it into specific shapes that can interact with a particular HMGS. The region of HMGS surrounding the guidance system varies across species and kingdoms potentially offering routes to designer inhibitors. Modifying the inhibitor in this way could yield analogs to treat high cholesterol with fewer side effects, said Noel.
Noel said that clinically important pathogenic bacteria such as Streptococcus pneumonia and Staphylococcus aureus also have versions of HMGS that could be targeted with related drugs. “Currently, there are no antibiotics that specifically target the mevalonic acid pathway and only a couple in very early development that target the related mevalonate-independent pathway – both of which we are exploring in earnest using the tools of structural biology and synthetic chemistry,” said Noel.
Noel and his colleagues have already begun synthesizing F-244 analogs to begin testing them to see if they possess more potent and more specific cholesterol-lowering or antimicrobial activity. Noel calls the approach “molecular dentistry” because his group is striving to shape inhibitory molecules to fit specific HMGS targets in much the same way that a dentist molds a filling to fit a patient’s tooth. Further work, he said, might focus on refining the compounds for use in agricultural applications, as fungicides or plant growth regulators since plants and fungi also possess the mevalonic acid pathway.
Authors who also contributed to this study include staff scientist Stéphane Richard, Ph.D., at the Salk, Jean-Luc Ferrer, Ph.D., at the Institut de Biologie Structural J.-P. Ebel in Grenoble, France, Dinesh A. Nagedowda, Mee-Len Dhye and professor Thomas J. Bach, Ph.D., at the Institut de Biologie Moléculaire des Plantes in Strasbourg, France.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
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