Signaling Proteins Boost Drug ActivitySignaling Proteins Boost Drug Activity

Scientists have successfully demonstrated that they can substantially enhance the activity of a drug by manipulating the effects of a particular group of proteins that are the linchpin molecules involved in bringing countless messages from the cell surface to its interior (Bonacci TM et al. Science. 2006;312:443-446). The strategy could potentially increase the effectiveness and precision of up to 60% of currently available drugs and result in fewer adverse effects.

These signal-relaying molecules, called heterotrimeric guanine nucleotide binding proteins (or G proteins for short), respond to hormones such as serotonin and acetylcholine as well as to sensory stimuli responsible for perception of light, smell, and taste. G proteins regulate multiple target proteins within the cell and mediate such processes as conducting nerve impulses, activating white blood cells, and modulating heart rhythm. Faulty G protein signaling has been implicated in various diseases, including diabetes, some hereditary endocrine disorders, and certain types of cancer.

Many drugs, including carvedilol for congestive heart failure, clozapine for schizophrenia, and ranitidine for heartburn, are designed to either shut down or enhance the function of receptors at the cell surface that are coupled with G proteins. But Alan Smrcka, PhD, of the University of Rochester Medical Center, in New York, and his team think smaller molecules that modulate the interactions of G proteins within cells could likewise be powerful and might provide more selectivity.

“Thirty to 60% of the drugs on the market are drugs that target G protein–coupled receptors,” said Smrcka, the study's principal investigator. “So by tickling the G proteins, you have the potential to modify the action of many agents.”

Research has shown that one particular location within G proteins—a so-called hotspot—tends to interact with enzymes more than any other location. After revealing the structure of this hotspot, Smrcka and colleagues applied software to screen databases of druglike molecules that might fit into different regions within the hotspot. They hypothesized that such differential targeting could allow for selective modulation of G protein functions.

The investigators performed a computer-simulated experiment to see which molecules from an existing database of 1990 known compounds would bind tightly to regions within the hotspot. The simulation revealed that subclasses of molecules did indeed bind to distinct subsurfaces of the hotspot and affected G protein interactions in different ways.

The researchers tested the in vivo effects of two of these compounds—M119 and M201—on white blood cell activation, one of the processes that G proteins control. Manipulating this process could help patients with diseases involving aberrant inflammation, such as rheumatoid arthritis or heart disease.

While both compounds bound with high affinity to similar surfaces within the hotspot, M119 was able to block a variety of different pathways in white blood cell activation, whereas M201 was specific for just one pathway. Smrcka's group is now planning to investigate why M119 and M201 exert these different effects, speculating that it may relate to differential binding to subsites within the hotspot.

“If we know why a particular compound targets one particular pathway, we can in the future focus our technology on that pathway and develop specific drugs for specific indications,” said Smrcka.

The researchers also tested M119's effects on pain relief, another process under the control of G proteins. M119 blocked activation of phospholipase C (an enzyme that plays a role in the effects of opioids) and provided an 11-fold increase in morphine's analgesic potency. The team plans to assess the effects that M119 and other compounds from their screen might have on other drugs as well.

This study demonstrates that “it is possible not only to identify small molecules that directly modulate the function of heterotrimeric G proteins, but also to find, with great efficiency, compounds that can turn off one signaling pathway while preserving or even augmenting others,” wrote John Joseph Grubb Tesmer, PhD, of the University of Michigan, in Ann Arbor, in an accompanying commentary (Tesmer JJG. Science. 2006;312:377-378). He added that such compounds could help elucidate the specific pathways regulated by G proteins under different physiological conditions and might lead to the development of new therapeutic agents.