Topographic Design of Peptide Neurotransmitters and Hormones on Stable Backbone Templates: Relation of Conformation and Dynamics to Bioactivity

Wieslaw M. Kazmierski, Henry I. Yamamura, Victor J. Hruby

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

We have proposed that development of methods for controlling the side-chain topography of amino acid residues in peptides and proteins provides a new approach to the topographical design of biologically active peptides. An example of this approach is the use of the 1,2,3,4-tetrahydroisoquinolinecarboxylic acid (Tic) residue, which favors a gauche (-) side-chain conformation when in the N-terminal position, whereas in its acylated form (internal position), the most stable side-chain conformation is gauche (+). This approach has been tested by incorporating D-Tic or Tic at different positions of μ opioid receptor specific octapeptides such as D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP, 1), examination of the biological consequences of these modifications, and detailed NMR based conformational analysis. The compounds prepared and their biological activities were as follows: D-Tic-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (2; gauche (-), /μ = 7800, IC50 μ = 1.2 nM); Gly-D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (3; gauche (+), /μ = 19, IC50 μ = 278.7 nM); and D-Phe- Cys-Tic-D-Trp-Orn-Thr-Pen-Thr-NH2 (4; gauche (+), /μ = ~7, IC50 μ = 1439.0 nM). In the absence of a geminal pair of protons suitable for distance calibration, a new technique (Davis, D. G. J. Am. Chem. Soc. 1987,109, 3471–3472) of transverse and longitudinal cross-relaxation rate measurements has been utilized in conjunction with other 2D NMR methods in order to determine the three-dimensional solution conformations for the peptides 1–4, with subsequent application of restrained molecular dynamics (gromos). The average backbone conformations in peptides 1–4 were very similar, but the side-chain conformational preferences in the analogues differed, suggesting that the different affinities and selectivities for μ opioid receptors were primarily due to differences in the side-chain conformations of Tic (d-T1c), and thus due to differences in the topographies of these peptides, and not the backbone conformations. A detailed analysis of these relationships is presented.

Original languageEnglish (US)
Pages (from-to)2275-2283
Number of pages9
JournalJournal of the American Chemical Society
Volume113
Issue number6
DOIs
StatePublished - Jan 1 1991

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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