Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites

Abstract

Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. Here, we first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1 iKO ) mice. We showed that heparan sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. Our glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, we identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential inhibitor for CCL20-heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vain or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine-heparan sulfate interaction in the asthma development and Di-S-IdoA as a potential drug for asthma treatment.

The Interaction of Heparin Tetrasaccharides with Chemokine CCL5 Is Modulated by Sulfation Pattern and pH

“…This and a number of other studies conducted over the last decade have provided convincing evidence that the interaction of chemokines with GAGs is a critical component of directed leukocyte migration (5). As a result, disruption of chemokine-GAG binding events have been targeted for the development of novel anti-inflammatory agents that are GAG analogs (6,7).…”

A Dilemma in the Glycosaminoglycan‐Based Therapy: Synthetic or Naturally Unique Molecules?

“…As Hp is the mostly used therapeutic GAG and serve as model compound to any other GAG type (especially HS) in both experimental and theoretical studies, the amount of works concerning synthesis of Hp is therefore way bigger than any other GAG type. [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] The second GAG most studied in terms of its synthetic routes is its sister molecule, HS. 54,55,[58][59][60][61][62][63][64][65][66] As described in Figure 1A, HS and Hp are both composed of GlcN units as hexosamine type and a UroA.…”

“…Some works have performed biological tests on the generated synthetic oligosaccharides as discussed below. [47][48][49][50][51][54][55][56][57]59 Oligosaccharides can be synthesized by modular approaches (Hp [42][43][44][45][46] and HS 58,59,63,65,68 ) as well as by chemoenzymatic methods (Hp 53-57 and HS 60,64,66 ).…”

“…50 Nonaka and co-workers have shown that synthetic disulfated IdoA has the capacity to attenuate asthmatic response by blocking T-cell recruitment into the inflamed sites. 57…”

Synthetic Oligosaccharide Libraries and Microarray Technology: A Powerful Combination for the Success of Current Glycosaminoglycan Interactomics

“…In glycosaminoglycanomics, for example, GAG‐like molecules (mostly oligosaccharides of well‐defined structures and sizes) have been successfully synthesized . GAG synthesis can be accomplished either by chemoenzymatic routes– or based on modular assembly of pre‐synthesized building blocks –––. Module‐based synthesis is sometimes used in conjunction with additional chemical and/or enzymatic steps to increase yield and diversity of sulfation patterns .…”