Design of low molecular weight hematoregulatory agents from the structure-activity relationship of a dimeric pentapeptide

J Med Chem. 1997 Aug 29;40(18):2876-82. doi: 10.1021/jm9702443.

Abstract

We report herein, a new class of simple hematoregulatory semipeptides, formally derived from the cystine-dimerized peptide pGlu-Glu-Asp-Cys-Lys-OH, where the disulfide bond has been replaced by an isosteric dicarba bridge. The structure-activity relationship (SAR) of a series of analogues incorporating replacements at positions 1 and 2 of peptide 1 led to the design of active conformationally constrained cyclic peptides (12, 13). Ring closure was achieved by cyclization of the N-terminal amino groups at position 2 of peptide 2 using pyrazine-2,3-dicarboxylic acid. Subsequent excision of the putative C-terminal scaffold domain from the active cyclic peptides resulted in the discovery of a new class of low molecular weight hematoregulatory agents exemplified by compound 16. This semipeptide analogue, comprising two D-Ser residues connected via amide bonds to the acid groups of pyrazine-2,3-dicarboxylic acid, had comparable biological activity to the lead peptide 1. The stereochemical requirements for the observed biological activity of these novel compounds were examined. Furthermore, the hematopoietic synergistic activity induced by compound 16 in stromal cell cultures was blocked by an antibody known to neutralize the hematoregulatory effect of 1, indicating a common mechanistic end point. Compounds of the class typified by 16 may form the basis for the development of novel therapeutic agents within the area of immunoregulation.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone Marrow Cells
  • Cell Line
  • Cells, Cultured
  • Colony-Forming Units Assay
  • Culture Media, Conditioned
  • Dimerization
  • Granulocytes / cytology
  • Hematopoiesis / drug effects*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects*
  • Indicators and Reagents
  • L Cells
  • Macrophages / cytology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Weight
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Stereoisomerism
  • Stromal Cells / cytology
  • Structure-Activity Relationship

Substances

  • Culture Media, Conditioned
  • Indicators and Reagents
  • Oligopeptides