Conformational and topographical considerations in the design of biologically active peptides

An outline of the basic considerations that are under development for the rational design of biologically active peptides and peptidomimetics is given. The necessary interplay of biophysical, chemical, and biological considerations is emphasized. The importance of properly designed biological assays to provide chemical information analogous to that from biophysical studies is discussed. The development of asymmetric synthesis in conjunction with conformational considerations for the preparation of specialized amino acids and amino acid mimetics is a critical aspect of the approach. The overall approach is illustrated with three examples from our laboratory: (1) the redesign of somatostatin to a highly potent and selective μ‐opioid receptor antagonist using conformational and topographical considerations in design and for obtaining insights into the pharmacophor; (2) the use of topographical considerations for obtaining oxytocin antagonists; and (3) the application of designer amino acids prepared by asymmetric synthesis to obtain insight into the topographical requirements at δ‐opioid receptors. © 1993 John Wiley & Sons, Inc.

[1]  V. Hruby.  Implications of the X-ray structure of deamino-oxytocin to agonist/antagonist-receptor interactions , 1987 .

[2]  T. Blundell,et al.  Crystal structure analysis of deamino-oxytocin: conformational flexibility and receptor binding. , 1988, Science.

[3]  V. Hruby,et al.  Asymmetric synthesis of topographically constrained amino acids: synthesis of the optically pure isomers of α,β-dimethyl-phenylalanine and α,β-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid , 1991 .

[4]  D. Barra,et al.  Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors. , 1989, European journal of pharmacology.

[5]  D. Barra,et al.  Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[6]  T F Burks,et al.  Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[7]  L. Terenius.  Somatostatin and ACTH are peptides with partial antagonist-like selectivity for opiate receptors. , 1976, European journal of pharmacology.

[8]  W. Vale,et al.  Regulatory peptides of the hypothalamus. , 1977, Annual review of physiology.

[9]  V. Hruby,et al.  Topographically designed analogues of [D-Pen,D-Pen5]enkephalin. , 1991, Journal of medicinal chemistry.

[10]  S. Sagan,et al.  Differential contribution of C-terminal regions of dermorphin and dermenkephalin to opioid-sites selection and binding potency. , 1989, Biochemical and biophysical research communications.

[11]  Design of Novel Cyclic Hexapeptide Somatostatin Analogs from a Model of the Bioactive Conformation , 1984 .

[12]  V. Hruby,et al.  Conformationally restricted analogs of somatostatin with high mu-opiate receptor specificity. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[13]  V. Hruby,et al.  Designing peptide and protein ligands for biological receptors. , 1991, Current opinion in biotechnology.

[14]  V. Hruby,et al.  A new approach to receptor ligand design: synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoouinoline carroxylic acid , 1988 .

[15]  V. Hruby,et al.  Topographic design of peptide neurotransmitters and hormones on stable backbone templates: relation of conformation and dynamics to bioactivity , 1991 .

[16]  V. Hruby,et al.  Conformational and dynamic considerations in peptide structure-function studies , 1982, Peptides.

[17]  G. Landis,et al.  Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with delta opioid receptor selectivity. , 1992, Journal of medicinal chemistry.

[18]  B. Montgomery Pettitt,et al.  The conformational properties of the delta opioid peptide [D-Pen2,D-Pen5]enkephalin in aqueous solution determined by NMR and energy minimization calculations , 1988 .

[19]  V. Hruby,et al.  Relative conformational rigidity in oxytocin and (1-penicillamine)-oxytocin: a proposal for the relationship of conformational flexibility to peptide hormone agonism and antagonism. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[20]  V. Hruby,et al.  Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for μ opioid receptors , 1986 .

[21]  V. Hruby,et al.  [D-Pen2,D-Pen5]enkephalin analogues with increased affinity and selectivity for delta opioid receptors. , 1990, Journal of medicinal chemistry.

[22]  D. Veber,et al.  The design of metabolically-stable peptide analogs , 1985, Trends in Neurosciences.

[23]  C. Toniolo.  Conformationally restricted peptides through short-range cyclizations. , 2009, International journal of peptide and protein research.

[24]  V. Hruby,et al.  Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations. , 1990, The Biochemical journal.

[25]  V. Hruby,et al.  Asymmetric synthesis of unusual amino acids: Synthesis of optically pure isomers of β-methylphenylalanine , 1989 .

[26]  V. Hruby,et al.  Conformation of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP-NH2), a highly selective mu-opioid antagonist peptide, by 1H and 13C n.m.r. , 2009, International journal of peptide and protein research.

[27]  Horst Kessler,et al.  Conformation and Biological Activity of Cyclic Peptides , 1982 .

[28]  C. Toniolo,et al.  Constrained phenylalanine analogues. Preferred conformation of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) residue. , 2009, International journal of peptide and protein research.

[29]  V. Hruby,et al.  Examination of the conformational meaning of “δ-address” in the dermenkephalin sequence , 1990 .

[30]  Gregory V. Nikiforovich,et al.  Topographical requirements for δ‐selective opioid peptides , 1991 .

[31]  V J Hruby,et al.  Conformational restrictions of biologically active peptides via amino acid side chain groups. , 1982, Life sciences.

[32]  V. Hruby,et al.  Asymmetric 1,4-addition of organocuprates to chiral .alpha.,.beta.-unsaturated N-acyl-4-phenyl-2-oxazolidinones: a new approach to the synthesis of chiral .beta.-branched carboxylic acids , 1993 .

[33]  M. Lebl,et al.  Conformationally restricted analogs of oxytocin; stabilization of inhibitory conformation. , 2009, International journal of peptide and protein research.