Synthesis and biological activity of tuftsin and rigin derivatives containing monosaccharides or monosaccharide derivatives

Abstract

Synthesis of some modified rigins is described in which either D‐gluconic acid or 2‐amino‐2‐deoxy‐β‐D‐glucopyranose have been linked to the parent molecule through amide bonds involving the α‐amino function, α‐carboxyl function or the γ‐amide function of glutamine in position 2. Glu2‐rigin and D‐gluconyl‐Glu2‐rigin have also been synthesized. Binding and phagocytosis assays have been carried out on the rigin derivatives and on some glycosylated tuftsin derivatives as well. Of all the tested peptides only rigin enhanced the phagocytic capacity of mouse peritoneal macrophages to the same extent as tuftsin. The peptides H‐Thr‐Lys‐Pro‐Arg‐NH‐Glc and Nα‐gluconyl‐Gly‐Glu‐Pro‐Arg‐OH slightly enhanced phagocytosis. H‐Thr[(α + β)‐O‐glucosyl]‐Lys‐Pro‐Arg‐OH was found to displace 3H‐tuftsin even better than tuftsin but lacked the ability to stimulate phagocytosis.

Determination of an unusual secondary structural element in the immunostimulating tetrapeptide rigin in aqueous environments: insights via MD simulations, 1H NMR and CD spectroscopic studies

“…Rigin, an immunostimulating tetrapeptide (Gly 341 ‐Gln‐Pro‐Arg 344 ) that connects the C H 2 and C H 3 domains of human IgG molecule, has been shown to exhibit significant in vitro phagocytosis‐stimulating activity toward rat blood leukocytes and Staphylococcus aureus 1–4. The reported phagocytosis index of rigin 1, 2 has been found to be same as that of another structurally related immunostimulating tetrapeptide, tuftsin (Thr 289 ‐Lys‐Pro‐Arg 292 ), located in the C H 2 domain, which has been extensively investigated for its structure–function relationship 3, 5–9. Rigin is capable of efficiently releasing interleukin‐1 and α‐tumor necrosis factor from human monocytes and displacing [ 3 H]‐tuftsin from macrophages at significantly high concentrations of ∼10 −4 M 2.…”

“…The reported phagocytosis index of rigin 1, 2 has been found to be same as that of another structurally related immunostimulating tetrapeptide, tuftsin (Thr 289 ‐Lys‐Pro‐Arg 292 ), located in the C H 2 domain, which has been extensively investigated for its structure–function relationship 3, 5–9. Rigin is capable of efficiently releasing interleukin‐1 and α‐tumor necrosis factor from human monocytes and displacing [ 3 H]‐tuftsin from macrophages at significantly high concentrations of ∼10 −4 M 2. To develop potent rigin derivatives capable of exhibiting enhanced phagocytosis activity, Rocchi et al 2 initially attempted the chemical synthesis and bioactivity evaluation of a few glycosylated derivatives; however, these failed to augment the phagocytosis‐stimulating activity.…”

“…Rigin is capable of efficiently releasing interleukin‐1 and α‐tumor necrosis factor from human monocytes and displacing [ 3 H]‐tuftsin from macrophages at significantly high concentrations of ∼10 −4 M 2. To develop potent rigin derivatives capable of exhibiting enhanced phagocytosis activity, Rocchi et al 2 initially attempted the chemical synthesis and bioactivity evaluation of a few glycosylated derivatives; however, these failed to augment the phagocytosis‐stimulating activity.…”

“…The presumption that endogenous peptide immunomodulators generate physiological responses in target cells via their specific surface receptor suggests that rigin may activate macrophage binding to its own specific receptor, i.e. other than tuftsin receptor 2. The two immunomodulators may be considered similar but not identical and such closely related peptide sequences provide excellent biological probes to elucidate biological processes for understanding their specific functions in living systems.…”

“…The two immunomodulators may be considered similar but not identical and such closely related peptide sequences provide excellent biological probes to elucidate biological processes for understanding their specific functions in living systems. Despite undoubted therapeutic potential utility of these immunomodulators, only limited reports exists in respect of rigin's structure–function relationships 2, 4, 10–12. Although the chemical identity of rigin has been described more than three decades ago, unlike with tuftsin 13, 14, no attempt has been made to identify and characterize the rigin receptor.…”