|In Drug Design, a Loose Fit May Be Best Bet
Chemical knockoffs resembling a key thyroid-related hormone are,
in certain cases, more effective than the real thing at activating
the target receptor, says a new study conducted in part by researchers
at the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) and the National Institute on Deafness and Other
Communication Disorders (NIDCD), two of the National Institutes
of Health (NIH). The improved performance is related to how closely
coupled the chemical and receptor are, the scientists conclude,
with a loose connection being more effective than a tight one.
The findings are at odds with the widely held notion that the stronger
the association between a hormone and its receptor, the more effective
its cellular signaling. If the findings hold true for similar hormone-receptor
reactions, they could help change the way that drug therapies are
designed for a host of health problems, from smell and taste disorders
to heart disease, asthma, migraine, and pain. The study is published
in the May 12, 2006, issue of the Journal of Biological Chemistry.
The researchers looked at thyrotropin-releasing hormone, or TRH,
a hormone released in the brain that kicks off a chain of events
throughout the body, including the stimulation of the thyroid gland.
As with many of the body’s hormones, cells recognize TRH using
a receptor belonging to a mega-family of proteins known as G-protein-coupled
receptors (GPCRs), which play a lead role in cell-to-cell communication.
When a hormone binds to its designated GPCR on the outside of a
cell, a specific G-protein is activated within the cell, initiating
a cascade of biochemical events leading to the unique and appropriate
cellular response to that hormone.
“GPCRs are the targets of roughly a third of medicines sold today,
so if this finding for TRH holds for other GPCR targets, it could
have significant implications for drug development,” says Marvin
C. Gershengorn, M.D., director of NIDDK’s Division of Intramural
Research and senior author of the paper.
“At first glance, a cellular process that affects the thyroid
gland may not seem especially meaningful to the study of communication
disorders,” says John Northup, Ph.D., who heads the Section on
Signal Transduction of NIDCD’s Laboratory of Cellular Biology. “However
this research provides information that is fundamental to cellular
signaling, a function that is essential to all cells in all systems
in the body, including our sensory systems of hearing, balance,
taste, and smell.”
By tweaking portions of the TRH molecule, the researchers developed
six slightly edited versions, while retaining most of the properties
of the natural hormone. Measuring the cellular response when hormone
meets receptor, they found that the lower the affinity between
the two, the stronger the signal that is elicited, with certain
analogs performing up to twice as effectively as TRH. As to why
this would be the case, the researchers suggest that a loose connection
between hormone and GPCR may allow a hormone to repetitively dock
to and undock from its associated GPCR, activating a succession
of G-proteins, and firing signal after signal. A tight connection,
alternatively, may tie up a hormone with its GPCR, activating one
G-protein, and limiting its signaling ability.
In future studies, the scientists hope to determine whether their
findings are consistent with other hormone-GPCR reactions. Other
researchers taking part in the study represent the National Institute
of Pharmaceutical Education and Research, Punjab, India.
NIDDK, part of the National Institutes of Health (NIH), conducts
and supports research on diabetes; endocrine and metabolic diseases;
digestive diseases, nutrition, and obesity; and kidney, urologic
and hematologic diseases. Spanning the full spectrum of medicine
and afflicting people of all ages and ethnic groups, these diseases
encompass some of the most common, severe, and disabling conditions
affecting Americans. For more information about NIDDK programs,
see the Web site at www.niddk.nih.gov.
NIDCD supports and conducts research and research training
on the normal and disordered processes of hearing, balance, smell,
taste, voice, speech and language and provides health information,
based upon scientific discovery, to the public. For more information
about NIDCD programs, see the Web site at www.nidcd.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.