'Plugs' For Drugs Promise Mightier Medicines


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Whether it's one pill several times a day or a self-administered injection, taking medicine frequently can be a major nuisance. Now Weizmann Institute scientists have developed a new approach that may prolong the action of many drugs, making it possible to administer them at much greater intervals without jeopardizing their effectiveness. Immediately after it's taken, the medication's levels in the blood normally surge -- sometimes up to 100 times more than what is needed.
Such high levels often produce damaging side effects, but they are necessary to keep the drug in the blood long enough to do its job. Then, within minutes to several hours, the drug is cleared from the circulation, creating the need for a new dose. For several decades, scientists have exerted major efforts to invent a way of releasing drugs into the blood in a more balanced manner while prolonging the time a medication actively circulates in the body. Unfortunately, this goal has been achieved for only a very limited number of drugs.

Prof. Mati Fridkin of the Organic Chemistry Department and Prof. Yoram Shechter of the Biological Chemistry Department have designed a new technique that can affect how numerous categories of drugs, including antibiotics and cancer medications, are released into the body.  The technique is based on a molecular "plug" that attaches to and temporarily blocks the action of the drug. Once the medication enters the circulation, the "plug" is gradually disconnected. This, the scientists believe, releases relatively low but steady quantities of the drug into the patient's blood over a long period of time. This approach may make it possible to administer a drug less frequently in significantly larger doses than usual without causing side effects. Contributing to the drug's prolonged action is the fact that medications modified with the "plug" are less susceptible to breakdown by enzymes than their unmodified counterparts.
In an animal study to be published in Diabetes, the researchers, working with graduate student Eytan Gershonov, demonstrated that their approach works well for insulin, a drug used by diabetics to normalize their blood glucose levels. When diabetic rats were given insulin modified with the molecular "plug," a single injection kept glucose levels at a normal level for two days. In contrast, a single injection of unmodified insulin produced the same effect for only 6-12 hours. The new "plug" is a small organic molecule widely used in the production of organic compounds. In the test tube, it slowly disconnects from the drug under the temperature and pH conditions equivalent to those prevalent in human blood. The scientists can create different versions of the molecular plug that can be disconnected at different rates, so that the speed of the drug release into circulation can be precisely controlled.

Currently, the Institute scientists are exploring an additional potential advantage of this technology. Test-tube experiments suggest that the organic plug may improve drug absorption by the intestines. If these findings are supported by further studies, the plug technology, which is covered by a patent, may be used to convert injected drugs into oral medications.

To commercialize the new method, a start-up company, LAPID Pharmaceuticals Ltd., has recently been formed by Pamot Venture Capital Fund and Yeda Research and Development Co. Ltd, the Weizmann Institute's technology transfer arm. Prof. Fridkin holds the Lester B. Pearson Chair of Protein Research, and Prof. Shechter, the Charles H. Hollenberg Chair of Diabetes and Metabolic Research.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.