Centrally Truncated and Stabilized Porcine Neuropeptide Y Analogs: Design, Synthesis, and Mouse Brain Receptor Binding

Porcine neuropeptide Y (pNPY) has been proposed to form an intramolecularly stabilized structure characterized by N- and C-terminal helical regions arranged antiparallel due to a central turn region. Analogs based on this structural model that have the central turn region and various amounts of the...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1989-06, Vol.86 (12), p.4377-4381
Main Authors: Krstenansky, John L., Owen, Thomas J., Buck, Stephen H., Hagaman, Karen A., McLean, Larry R.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Aminoacids, peptides. Hormones. Neuropeptides
Analytical, structural and metabolic biochemistry
Animals
Biochemistry
Biological and medical sciences
brain
Brain - metabolism
Circular Dichroism
Crystal structure
Disulfides
Drug Design
Drug Stability
Fundamental and applied biological sciences. Psychology
Indicators and Reagents
Mice
Models, Molecular
Molecular Sequence Data
Molecules
Neuropeptide Y - analogs & derivatives
Neuropeptide Y - chemical synthesis
Neuropeptide Y - metabolism
Neuropeptides
Protein Conformation
Proteins
Receptors
Receptors, Neuropeptide Y
Receptors, Neurotransmitter - metabolism
Resins
Species Specificity
Truncation
Citations: Items that cite this one
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Description
Summary:Porcine neuropeptide Y (pNPY) has been proposed to form an intramolecularly stabilized structure characterized by N- and C-terminal helical regions arranged antiparallel due to a central turn region. Analogs based on this structural model that have the central turn region and various amounts of the helical regions removed, yet retain the N and C termini in a similar spatial orientation were designed. The gap formed by removal of the central residues (residues 8-17 or 7-20) was spanned with a single 8-aminooctanoic acid residue (Aoc) and the structure was further stabilized by the introduction of a disulfide bridge. [D-Cys7,Aoc8-17,Cys20]pNPY and [Cys5,Aoc7-20,D-Cys24]pNPY were synthesized and found to have receptor binding affinities of 2.3 nM and 150 nM, respectively, in mouse brain membranes (pNPY affinity is 3.6 nM in this assay). It is proposed that the central region (residues 7-17) of pNPY serves a structural role in the peptide and is not involved in direct receptor interaction.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.86.12.4377