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Study Holds Promise For A New Approach To Drug Therapy

 
  April, 25 2006 20:44
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Researchers believe they have found a way to change the action of 60 percent of currently available medications, in some cases making them many times more effective, according to an article published in the April 21 edition of the journal Science. The discovery has the potential to improve treatments for diseases including heart disease, cancer, diabetes, depression and arthritis. The study describes a new way to manipulate perhaps the most important signaling mechanism in human cells: G-protein coupled receptors (GPCRs).

Human cells must be able to send signals that switch life processes on and off as they react to the nutrients, toxins, hormones and even the light particles they are exposed to. GPCRs are a key part of such signaling cascades, passing on messages that make vision possible, carry nerve messages, enable white blood cells to attack infection and set the timing of the heartbeat. Faulty GPCR signaling, on the other hand, plays a key role in several major diseases. As a result, GCPRs are targeted by 12 of the top 20 selling drugs, including Coreg for congestive heart failure, Cozaar for high blood pressure, Zoladex for breast cancer, Buspar for anxiety and Clozaril for schizophrenia, as well as by Zantac and Claritin. Together the drug class accounts for $200 billion in annual sales.

Authors of the current study believe they have found a new way to regulate the same GCPR pathways, but at different points. Where most drugs change the behavior of GPCRs on the outside of cells, the new class of drugs seeks to influence related signaling on the inside. Early studies suggest that the newly discovered “drug candidates” can provide better control of pathways involved in pain relief, inflammation and heart disease, while leaving healthy functions in place.

“We believe we have discovered a new class of drugs that could make current drugs more effective, but that also represents a completely new, independent way of treating the same diseases,” said Alan V. Smrcka, Ph.D., associate professor of Pharmacology, Physiology, Oncology, Biochemistry and Biophysics at the University of Rochester Medical Center. “Early, pre-clinical experiments, for example, have found that one of our compounds can make morphine 11 times more potent,” said Smrcka, the article’s lead author. He was careful to point out that the new drugs still face many hurdles before they can be used in the clinic.

Signaling Workhorse

GPCRs are a part of a process wherecells convert one kind ofsignal received on their surfaces into another set of signals inside them. Proteins called receptors are built into the outer cell surfaces and designed to react with a single, specific signaling molecule (a ligand). When a signaling molecule docks into the receptor and binds to it, like a ship coming into port, it changes the shape of the dock in a such a way as to set off chain reactions inside the cell, enabling the cell to respond to the message. Ligands can be nutrients, toxins, hormones, etc.

The workhorses of this signaling process are transmembrane receptors like GPCRs. These proteins weave into and out of a human cell's outer membrane, with some parts of the receptor exposed to the cell’s outside and others exposed to its interior. When a GPCR, for example, binds to its ligand on the outer surface of the cell, the receptor allows parts of itself, the G protein, to break away on the inside of the cell, kicking off a series of reactions there.

Once free, a G protein itself breaks up into an alpha subunit and a tightly paired gamma-beta subunit. G proteins subunits, in effect, pass on the biological message inside the cell sent by the ligand that activates a GPCR on the outside. The free G protein gamma-beta subunit can, for example, “turn on” key target enzymes like phospholipase C and phosphoinositide 3 kinase. In white blood cells, the beta-gamma subunit binds to phosphoinositide 3 kinase, sending a signal that the cell needs to move in on and attack invading viruses. In heart muscle cells, a similar mechanism controls heart beat rate.

Many current, best-selling drugs work by binding to G-protein-coupled transmembrane receptors in the place of ligands on the outside of cells. A successful drug will either shut down or turn up the function of the GPCR as compared to its natural binding partner, whatever is called for to solve the problem. Dr. Smrcka’s team has been asking the question: what if, along with current drugs that interfere with disease on the outside of a cell membrane, we could also design drugs that interfere with the same pathway later in the process, when the disease-causing signal has passed from ligand to GPCR to the G protein subunit to enzymes within the cell?

Study Methods

Medical center researchers have been studying G proteins since 1994 because they exert control over so many proteins in so many cell types. Early tests revealed the existence of one location on the beta-gamma subunit in particular, a flexible “hotspot” where the majority of the subunit’s interactions with enzymes take place. Past studies have mapped the surface of the G protein, but medical center researchers were the first to conceive that it includes a hotspot, a multi-purpose binding site, for protein-protein interaction. Such a hotspot would represent a crucial new target for anyone trying to manipulate the G protein subunit to fight disease.

In the current study, researchers had to first solve the structure of the hotspot before they could apply software to screen through databases of “drug-like molecules” to identify those that fit into, and bound tightly to, specific parts of the hotspot. These “drug-like” molecules could then be used to make precision changes in the hotspot’s behavior. Any new drug would need to be able to block certain functions of the hotspot, while leaving the others in place. It would also have to be small enough to cross through the cell membrane and have its effect inside the cell.

Smrcka’s team performed a computer-simulated experiment to see which drug-like molecules from an existing database of 1990 known structures would bind tightly to the hotspot, and to rank them. In general, tight binding suggests that a drug candidate has the potential to remain bound to its target long enough to have the desired effect. Of the compounds found through the screen, one, called M119, had a high enough affinity for the hotspot to be chosen as a lead compound in further experiments. In a standard drug discovery technique, researchers collected several compounds (21 in this case) similar to their lead compound to see if any small change to the lead would drastically affect its drug potential.

Researchers tested two compounds as a proof of general principle, M119 and M201, which bound most effectively to the hotspot. For the purposes of the experiment, researchers chose to test the affect of M119 and M201 on two biological systems that the G protein gamma-beta subunit controls. In one, white blood cells home in on the site of infection. The other involves pain relief brought about by morphine.

In white blood cells, the free G protein gamma-beta subunit activates enzymes that allow the cells to home in on the site of infection. Researchers found that pre-treatment of white blood cells with M119 reduced activation of enzymes that encourage inflammation. That should in theory keep the white blood cells from mistakenly causing inflammation as they do in patients with rheumatoid arthritis or heart disease. While M119 did block the action of an enzyme involved in inflammation (PI3kinase), it did not block related signals necessary for basic cell function.

In addition, M119 was shown to block activation of phospholipase C, which plays a role in morphine’s ability to provide pain relief. In early studies, administration of M119 with morphine resulted in an eleven-fold increase in the analgesic potency of morphine. Researchers believe it does this by binding to the hotspot, and blocking the G gamma beta subunit’s ability to activate phopholipase C, which in turn inhibits pain signals.

“Imagine if we could identify 50 small molecules, with each one bringing about a specific set of changes in the behavior the hotspot,” Smrcka said. “Taken together, this arsenal would grant us precise control over one of the most important biochemical switches in the body. This area of study is so important because of the sheer number of drugs already on the market that could be made more effective by differential targeting.”

© Copyright University of Rochester Medical Center, 2006

Bonacci TM, Mathews JL, Yuan C, Lehmann DM, Malik S, Wu D, Font JL, Bidlack JM, Smrcka AV.
Differential targeting of Gbetagamma-subunit signaling with small molecules.
Science. 2006 Apr 21;312(5772):443-6.


Message posted by: Frank S. Zollmann

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