DEVELOPMENT OF PEPTIDE MODELS OF BETA ENDORPHIN

Project Details

Description

The long-term objectives of the project are to develop a thorough
understanding of the functional conformations of the opioid peptides
beta-endorphin and dynorphin A(1 -17), and the selectivities of these
ligands for binding and activating mu- delta- kappa- and epsilon-opioid
receptors. This-knowledge will be useful in the design of opioid peptides
and mimetic with novel receptor selectivities, enhanced potencies and
specificities, and varied agonist-antagonist character.

A model for the functional conformations of beta-endorphin and dynorphin
has been developed, based on the expectation-that interface-induced,
amphiphilic structures in these peptides will bind to the
hydrophilic/lipophilic interface of the cell surface. The first receptor
(a delta receptor) has also recently been cloned, and tentative models
for its gross structural features, including seven transmembrane alpha-
helices, are also already proposed. In this project period, opioid
peptide-receptor interactions will be probed in three ways, in order to
further develop, test and possibly combine both the ligand and the
receptor models: (i) A new approach, involving the incorporation of
peptide ligands into surface loops on a large globular protein by genetic
engineering, will be developed and applied to opioid receptors. In this
method, the "guest" -peptide ligand effectively ties its "host" protein
near to the ligand binding site. Steric and electrostatic information
concerning the receptor surface is then obtained by monitoring receptor
affinity as the host protein structure is altered. (2) Synthetic peptide
segments of the delta-opioid receptor, and others as they are cloned and
sequenced, will be used to test for protein folding interactions and
disulfide bridging between (a) the proposed transmembrane helices in
model lipid environments, and (b) the extracellular loops in aqueous
solution. For the extracellular loops, detailed synthetic models
incorporating loop-mimicking conformational constraints and helix
initiating structures will-be developed, and interactions with peptide
ligands will also be explored. (3) Synthetic chemistry developed earlier
in the project will be applied to the design of covalent bridges linking
residue pairs in the i-th and (i+7)-th positions in the amphiphilic
alpha-helix proposed as a membrane-binding and receptor-activating
element in (beta-endorphin. Such bridges, if successful for helix
stabilization, should be generally applicable in peptide mimetic design.
StatusFinished
Effective start/end date12/31/898/31/98

Funding

  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse

ASJC

  • Chemical Engineering(all)
  • Structural Biology
  • Biochemistry
  • Pharmacology

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