Peptide discovery and therapeutic development
Research Overview
The research in the Aldrich laboratory focuses on the design, synthesis and evaluation of peptide and peptidomimetic ligands, particularly for opioid receptors. In addition to synthesizing peptides and peptidomimetics for structure-activity relationship (SAR) studies, our laboratory is involved in synthetic method development and examining the pharmacokinetic (PK) properties of the peptides, including studying their ability to cross the blood-brain barrier (BBB) and other biological barriers. The opioid pharmacology of the peptides is examined in collaboration with colleagues at the University of Florida and elsewhere. We also perform some biological evaluation of the peptides in our lab.
Kappa opioid receptors (KOR) as a target for drug discovery
A primary focus of our research is peptidic ligands for kappa opioid receptors (KOR). In addition to the potential application of compounds with KOR agonist activity as analgesics, KOR antagonists are being explored as potential treatments for substance abuse. The KOR system and its endogenous agonists are involved in the response to stress, which is a major trigger for relapse to substance abuse. Therefore we are exploring KOR antagonists as an approach to prevent relapse to substance abuse in individuals who have discontinued taking addictive substances.
While several small molecule KOR antagonists have been identified and characterized over the years, the prototypical selective KOR antagonists have exceptionally long durations of action, lasting for weeks to a month depending on the species, after a single dose. This could be problematic for clinical application of such compounds, and compounds with more finite durations of action could be more readily developed. The degradation of peptides can be controlled by appropriate choice of structural modifications to provide compounds with the desired finite duration of action, and therefore we are examining peptide ligands for KOR. We are currently exploring two classes of peptides with activity at opioid receptors – dynorphin analogs and macrocyclic tetrapeptides. We are also exploring anti-cancer activity of the macrocyclic tetrapeptides.
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