PROTEIN ENGINEERING--PEPTIDE HORMONE DESIGN

Project Details

Description

The importance of potential regions of amphiphilic secondary
structure in determining the biological functions of peptide
hormones will be determined. The natural peptides to be studied
as examples include the serum calcium regulator calcitonin and
peptides involved in behavior modification, epithelial ion
transport, blood pressure regulation and other important effects,
including calcitonin gene-related peptide, and the neuropeptide
Y/peptide YY/pancreatic polypeptide family. In these cases,
potential amphiphilic alpha helices will be the first structures
studied in relation to a variety of possible roles, including
determination of receptor binding affinity and specificity,
participation in folded tertiary structures, and the control of
pharmacokinetic behavior in vivo, including proteolytic
degradation. Two approaches will be employed. An investigation
will be initiated into the design of amphiphilic alpha-helical
peptides that have conformational constraints involving cyclic
structures or non-natural amino acids chosen to stabilize the
helical conformation. In addition, the novel approach of designing
and synthesizing peptide models will be adopted, in which the
potential for amphiphilic helix formation will be retained in an
idealized form using amino acid sequences having minimal
homology to the corresponding natural sequences. Functional
importance will be determined by comparing the natural hormones
to analogs containing the best helix-promoting constrained
structures or the model sequences, in order to determine
correlations between the analog design and their physicochemical
and pharmacological properties. This approach will be extended
to other potential conformational features of these hormones
that, like the amphiphilic helices, are not readily identified in
aqueous solutions but may be important in the functional
environment. Ultimately, the arrangement of all structural
segments of these peptide hormones on their receptor surfaces
will be probed through the synthesis of conformationally
constrained peptide analogs that may include idealized models of
several conformational features such as alpha helices, beta turns,
collagen-like helices and flexible "random coil" structures,
composed by both natural and non-natural amino acids. These
studies should allow the rational design of potent and specific
agonists and antagonists with predictable pharmacokinetic
behaviors that might be useful as pharmacological tools or even
therapeutic agents. The lessons learned should be widely
applicable to the engineering of proteins in general.
StatusFinished
Effective start/end date4/1/8812/31/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $155,596.00

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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