Available Technology
Photoactivatable opoid neuropeptides
Technology:
Photoactivatible compounds
Markets Addressed
In addition to use in research for evaluating a neuronal response to a neuropeptide, caged neuropeptides may also have the following therapeutic applications:
• Modulation of neuronal activity in the brain or spinal cord to control pain, humger, seizures, attention, cognition. Light energy may be delivered by fiber optic stimulation of specific brain regions at specific times.
• Local application of a caged neuropeptide on or in the skin to control pain and/or inflammation. Light energy may be delivered via UV lamp to activate the peptide.
Innovations and Advantages
Background: Neuropeptides have profound and complex neuromodulatory effects on neuronal function in the mammalian nervous system. Neuropeptides, including Orexins, Leptin, Ghrelin and Neuropeptide Y, regulate sleep, appetite and energy metabolism. A number of drugs that target peptide receptors are used therapeutically for the treatment of disease. Despite their importance in human biology and disease, there is a poor understanding of how neuropeptide signaling regulates synapses and brain circuits. Studies into neuropeptide systems have been limited by a lack of experimental tools. Due to their large size and hydrophobicity, acute administration of neuropeptides in brain tissue produces a slowly rising, prolonged and spatially imprecise presentation of peptide with poor control over concentration. This can lead to aberrant receptor desensitization and hinders biophysical studies in intact tissue preparations.
Development of photoactivatable neuropeptides: To enable delivery of neuropeptides with micron-scale resolution, the Sabatini laboratory developed photoactivatable neuropeptides. The compounds are comprised of a neuropeptide agonist linked to a chemical group forming a cage structure that blocks the activity of the peptide. Exposure to UV light cleaves the caging structure and releases the neuropeptide agonist. Building on known pharmacology, the lab designed several candidate caged analogues of Leu- Enkephalin, a member of the opioid family of neuropeptides which is selective for the Delta and Mu opioid receptor subtypes.
Dose-response relationships identified caged analogues that exhibited >100 fold reductions in potency with respect to Leu-Enkephalin at both Mu and Delta receptors with no activity at Kappa receptors. For each analogue, photolysis was studied using UV/VIS spectroscopy, HPLC and mass spectrometry. Preliminary electrophysiological evaluation was carried out on inhibitory neurons in mouse hippocampal slices, the predominant cells expressing Mu and Delta opioid receptors in the CA1 region. Their findings indicate that CYLE, one of the caged neuropeptides, demonstrates:
• Photorelease of L-Enk: HPLC chromatograms of CYLE before and after exposure to UV light reveal photoconversion to L-Enk.
• High spatial resolution: CYLE rapidly and efficiently photoreleases L-Enk in brain tissue with ~100 µm spatial resolution.
• High temporal resolution: Because microsecond flashes of light can be delivered on the scale of single synapses with millisecond kinetics, neuropeptides can be released on the timescale of vesicular fusion with sub-cellular spatial precision.
• Graded delivery of L-Enk: Importantly, the concentration of released peptide is easily regulated by varying light intensity.
Additional Information
Intellectual Property Status: Patent(s) pending
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Inventor(s):
Banghart, Matthew R.
Sabatini, Bernardo
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For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #3538