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| Aldrich Unlocks Peptide Potential Like a key in a lock, a peptide ligand inserted into a receptor on the surface of a cell causes changes within the cell. Cellular changes cannot be seen on the surface. Yet, the changes occurring within open doors to treatments and cures for some of today’s most prevalent health concerns. Peptides that trigger opioid receptors can help curb drug addictions or provide non-addictive pain relief and anti-inflammatory benefits. Unlocking the potential of peptides is a growing area of scientific research worldwide. In the laboratory of Dr. Jane Aldrich at the University of Kansas, opioid peptide analogues are synthesized, and both standard approaches and combinatorial chemistry are used to identify novel peptides and peptidomimetics with affinity for opioid receptors. There are three major types of opioid receptors, mu, kappa, and delta. All opioid receptors share key similarities, and have a common general structure; they are G protein-coupled receptors embedded in the plasma membrane of neurons. Once a ligand binds to the receptor, a portion of the G protein is activated. The G protein interacts with its target - either an enzyme or an ion channel. These targets may alter protein phosphorylation, altering short-term neuronal activity, or alter gene transcription which acts over a longer timescale. Peptides are short pieces of proteins of approximately fifty or fewer amino acids. When a peptide ligand has affinity for a receptor, it is able to attach to that receptor. Not all peptides that are able to attach to a receptor are also able to activate it. Like keys that fit but don’t turn the lock, some peptides block the receptor. An agonist peptide is one that activates the receptor, while an antagonist blocks the receptor from being activated. One of the great strengths of peptides as potential therapies lies in the ease in making changes to their structure to optimize their activity. The ability to manufacture molecules with unnatural sequences can result in peptides that can differentiate between closely related targets. Furthermore, unnatural sequences may exhibit higher metabolic stability in vivo. “To develop these peptides as drugs,” says Aldrich, “we need to know how they work in the body.” Combinatorial peptide libraries provide Aldrich with new tools for both identifying and evaluating an exciting array of potential new opioid receptor ligands. In one project, Aldrich and her associates are synthesizing analogues of the opioid peptide dynorphin A, examining both the structure-activity relationships and the conformational requirements for agonist versus antagonist activity. Dynorphin A is a naturally occurring peptide that is an agonist at kappa opioid receptors. Kappa receptors are generally associated with analgesia, but activation of these receptors in the brain may also produce dysphoria. Kappa receptors are also located in the periphery; activating these receptors can result in pain relief and anti-inflammatory activity without dysphoria. Blocking kappa opioid receptors can result in antidepressant activity and may be useful in the treatment of drug addiction. One of Aldrich’s recent studies involving dynorphin A and a focused parallel combinatorial peptide library yielded some unexpected results. Modifications were made in the N-terminal sequence of arodyn, a dynrophin A analogue that is a kappa receptor selective antagonist. This combinatorial peptide library was designed and synthesized to identify analogues with higher kappa opioid receptor affinity. Several peptides displayed substantially higher kappa opioid receptor binding affinity than arodyn. Unexpectedly, two of these compounds exhibited almost full agonist activity. “The identity of the residues in the N-terminal sequence of arodyn analogues influence not only kappa receptor affinity and selectivity, but also efficacy,” explains Aldrich. “The identity of the residue in position 3 in these arodyn analogues appears to strongly influence the ability of the peptides to activate kappa opioid receptors.” The preliminary studies have revealed some unique results that have prompted additional studies. A second project involves developing appropriate synthetic strategies to incorporate reactive functionalities and various labeling groups into peptides, and synthesizing analogues of opioid peptides as affinity labels for opioid receptors. Affinity labels bind irreversibly to their target proteins and can be valuable tools in studying receptor –ligand interactions and receptor function. The long-term goal of this research is to identify the points of attachment of the affinity labels to opioid receptors. This will provide information at a molecular level on how peptide ligands interact with opioid receptors. “There are no X-ray structures of opioid receptors,” says Aldrich, “so we’re trying to crosslink a peptide to a receptor and figure out the attachment point.” By isolating these receptors, Aldrich and her group hope to identify key interactions in an effort to reduce side effects and as a basis for designing future synthetic compounds. “We may be able to control the receptor-ligand interactions by changing the structures,” says Aldrich. “Right now, these are all early-stage studies.” With scientists like Aldrich helping to unlock their therapeutic potential, peptides are certain to provide the key to important new drugs in the future.
Higuchi
Biosciences Center |
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