Design of Low Molecular Weight Hematoregulatory Agents from the Structure−Activity Relationship of a Dimeric Pentapeptide

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semipeptides, formally derived from the cystine-dimerized peptide pGlu-Glu-Asp-Cys-Lys-OH, where the disulfide bond has been replaced by an isosteric dicarba bridge.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.

The Crystal Structure of N,N′-Bis-(1,3-dihydroxy-2-methylprop-2-yl)- pyrazine-2,3-dicarboxamide Semihydrate

“…Of particular interest to the pharmaceuti cal industry are low molecular weight hematoregu latory agents, which offer the same benefits as the larger protein drugs but also have added advantages such as stability and oral bioavailability. During a structure-activity relationship study [3] on a novel hematoregulatory nonapeptide (1, (Pyr-Glu-Asp)2-DAS-(Lys)2) compound 2 comprising pyrazine-2,3-dicarboxylic acid linked to two D-serine residues via amide bonds was discovered [4], This much simplified structure was found to be a highly po tent inducer of a hematopoietic synergistic fac tor (HSF) known to enhance colony formation in a GM-CFC colony forming assay [5]. Direct re placement of the D-Ser residues with 2-amino-2-methyl-1,3-propanediol and 2-amino-2-methyl-1,3-propanediol led to the achiral semi-peptide ana logues 3 and 4 with full biological activity.…”

Novel cyclic peptide inhibits intercellular adhesion molecule‐1‐mediated cell aggregation

“…Disulfide bonds connecting the N‐ and C‐terminus can lead to longer serum half‐lives, presumably by preventing proteolysis, and increasing the rigidity of the structure yields higher affinity compounds (25–28). As a result, cyclic peptides have been shown to be effective inhibitors in vivo of integrins related to LFA‐1 in human and animal disease (26,29–34). Furthermore, cyclic peptide inhibitors may be used as lead structures to develop improved next‐generation antagonists (35–37).…”