Exploring the Anti-Inflammatory Potential of a Peptide Mimetic of Sialic Acid(\(\alpha\)2,3) Galactose
Recent Developments in Chemistry and Biochemistry Research Vol. 5,
25 July 2024
,
Page 152-182
https://doi.org/10.9734/bpi/rdcbr/v5/1744
Abstract
A tetravalent peptide with the functional sequence NPSHPLSG designated svH1C, binds with high avidity to lectin-type receptors specific for structures that contain sialic acid (5-acetylneuraminic acid, Neu5Ac). Among the sialic acid-binding immunoglobulin-like lectins (the Siglec family of receptors), the peptide binds preferentially to those that bind Neu5Ac(\(\alpha\)2,3)Gal and Neu5Ac(\(\alpha\)2,8) Neu5Ac(\(\alpha\)2,3)Gal sequences and the larger sialyl Lewisx (sLex) structure. svH1C has a flexible structure that enables binding with high avidity in the glycan binding site in an ‘induced-fit’ conformation. Peritoneal populations of cells in C57BL/6 mice that constitute the innate immune system were increased 2- to 6-fold after three alternate-day subcutaneous injections. Incubation of neuraminidase-treated, human peripheral blood mononuclear cells with biotin-tagged svH1C resulted in substantial binding of the peptide to a subset of the CD14+ monocyte population. Nanomolar concentrations of svH1C induced phagocytic activity of adherent cells (monocytes and macrophages) from PBMC cultures. Predictions by molecular modeling suggest that the peptide binds to P- and E-selectins, which are receptors that facilitate the migration of neutrophils and T cells through endothelial tissues, and to siglecs on macrophages with avidities that are expected to mitigate neutrophil-driven inflammation. The therapeutic value of these anti-inflammatory activities was demonstrated by the resolution of severe lipopolysaccharide-induced inflammation in the skin of mice in two weeks by daily subcutaneous injections of 1 nmol/g body weight. These results support the conclusion that svH1C mimics Neu5Ac(\(\alpha\)2,3) Gal sequences and interacts with glycan binding sites of specific receptors with avidities sufficient to promote repair and restoration of damaged tissues.
- Sialic acid mimetics
- siglecs
- selectins
- NKG2D
- STAT6
- phagocytosis
- inflammation
- neutrophils