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Research |
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Like serotonin, neuropeptides are signaling molecules within the brain and gastrointestinal tract. Problems with signaling often cause health problems. Despite the prevalence of neuropeptides within the brain and their importance, they are often poorly characterized under physiological conditions. Our research aims to provide key structural characteristics of neuropeptides under physiological conditions for the sake of aiding the rational design of therapeutics. Please see below for more detail. |
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Neuropeptides are found within neural tissue and bind to transmembrane G-protein coupled receptors (GPCRs). A given neuropeptide may interact with multiple receptors, each inducing unique effects within the nervous system. That they function as ligands to GPCRs, despite their often unstructured or only partially structured nature, is impressive. Whether the partially structured site displays a recognition motif is an open question. Directly identifying the functionally important characteristics of a given neuropeptide has been difficult because under physiological conditions they are primarily unstructured, which makes it rather challenging to obtain structural information for rationally designing therapeutics.
This research will target endomorphins, four amino acid neuropeptides where a fundamental structural question relates to the cis-trans amide isomerization of an amino acid (proline). Under physiological conditions, endomorphin structural characteristics are unknown, e.g. potential cis-trans proline isomerization might play an important role in receptor binding. Site-specific carbon-deuterium (C-D) labeled neuropeptides will be synthesized and undergo spectroscopic characterization (IR, circular dichroism and NMR). The insights gained from these studies will help unravel the complex nature of neuropeptide structure and specificity, which would ideally translate into more facile design of highly selective agonists and antagonists. |
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Neuropeptides: neuroscience for the organic chemist |
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Support comes from Gonzaga University start-up funds, the Gonzaga Science Research Program, and in part by a grant to Gonzaga University from the Howard Hughes Medical Institute through the Undergraduate Science Education Program.
Acquisition of a CD spectrometer was supported by the National Science Foundation under CHE-0922945 (“MRI: Acquisition of a Spectropolarimeter: A Chiro-Optical Spectroscopy Workbench” $181,155; 2009-2012; PI: Cremeens with co-PIs Jeff Watson and Tommaso Vannelli.) |
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Funding |
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Neuropeptides are synthesized by solid-phase peptide synthesis, purified by HPLC, and characterized by infrared spectroscopy (IR), circular dichroism, and 2-D nuclear magnetic resonance (NMR) experiments.
Spectroscopic observations are compared to quantum chemical calculations using GAMESS, NWCHEM and the WebMO interface on an Intel cluster at Gonzaga University, which is part of the Intel Corporation Computational Science Laboratory. A collaboration with the Corcelli Lab at Notre Dame provides additional theoretical insights into our spectroscopic observations.
Raman spectroscopy is also used to explore our systems via a collaboration with the Desamero Lab at York College. |
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Methods: Synthesis, Spectroscopy, and Calculations |
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Cartoon of a deuterated peptide |
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Crystal structure of a GPCR (PDB: 1F88). |
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Deuterium (D) |