Selectin antagonists and their potential impact for the treatment of inflammatory lung diseases

Aydt, Ewald M.; Bock, Daniel; Wolff, Gerhard

doi:10.1159/000320817

Cited by 4 publications

(5 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different types of strategies were used to design selectin antagonists, including carbohydrates, glycomimetics, non-carbohydrate small molecules, macromolecules, peptides, monoclonal antibodies, and DNA-aptamers. These efforts were reviewed recently [11,20,256,304,305,[318][319][320][321][322][323][324].…”

Section: Glycomimetic Inhibitorsmentioning

confidence: 99%

“…Over the last three decades, numbers of small-molecule inhibitors of selectins have been reported with varying potency and many of them have been validated in animal models. However, despite this enormous effort, only a few compounds have entered clinical trials, usually without success [20,176,304,320,324]. Some examples of recently developed small-molecule selectin inhibitors are given in Figure 15.…”

Section: Compounds In Clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

2020

View full text Add to dashboard Cite

Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLex is an essential glycan recognized by selectins. Several glycosyltransferases are responsible for the biosynthesis of the sLex tetrasaccharide. Selectins are involved in a sequence of interactions of circulated leukocytes with endothelial cells in the blood called the adhesion cascade. Recently, it has become evident that cancer cells utilize a similar adhesion cascade to promote metastases. However, like Dr. Jekyll and Mr. Hyde’s two faces, selectins also contribute to tissue destruction during some infections and inflammatory diseases. The most prominent function of selectins is associated with the initial stage of the leukocyte adhesion cascade, in which selectin binding enables tethering and rolling. The first adhesive event occurs through specific non-covalent interactions between selectins and their ligands, with glycans functioning as an interface between leukocytes or cancer cells and the endothelium. Targeting these interactions remains a principal strategy aimed at developing new therapies for the treatment of immune and inflammatory disorders and cancer. In this review, we will survey the significant contributions to and the current status of the understanding of the structure of selectins and the role of selectins in various biological processes. The potential of selectins and their ligands as therapeutic targets in chronic and acute inflammatory diseases and cancer will also be discussed. We will emphasize the structural characteristic of selectins and the catalytic mechanisms of glycosyltransferases involved in the biosynthesis of glycan recognition determinants. Furthermore, recent achievements in the synthesis of selectin inhibitors will be reviewed with a focus on the various strategies used for the development of glycosyltransferase inhibitors, including substrate analog inhibitors and transition state analog inhibitors, which are based on knowledge of the catalytic mechanism.

show abstract

Section: Glycomimetic Inhibitorsmentioning

confidence: 99%

Section: Compounds In Clinical Trialsmentioning

confidence: 99%

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

2020

View full text Add to dashboard Cite

show abstract

“…Numerous studies have demonstrated the essential role of selectins and their ligands in inflammatory lung diseases, including ARDS, chronic obstructive pulmonary disease and asthma ( Romano and Slee 2001 ; Tvaroška et al. 2020 ), and the potential of using inhibitors of selectins in their treatment ( Woodside and Vanderslice 2008 ; Aydt et al. 2010 ).…”

Section: Introductionmentioning

confidence: 99%

“…2007 ; Ludwig et al. 2007 ; Ernst and Magnani 2009 ; Aydt et al. 2010 ; Bedard and Kaila 2010 ; Wang and Vidal 2013 ; Videira et al.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pan-selectin inhibitors as potential therapeutics for COVID-19 treatment: in silico screening study

et al. 2021

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the globe. The spectrum of disease is broad but among hospitalized patients with COVID-19, respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. There is an urgent need for an effective treatment. The current focus has been developing novel therapeutics, including antivirals, protease inhibitors, vaccines, and targeting the overactive cytokine response with anti-cytokine therapy. The overproduction of early response proinflammatory cytokines results in what has been described as a “cytokine storm” is leading eventually to death when the cells fail to terminate the inflammatory response. Accumulating evidence shows that inflammatory cytokines induce selectin ligands that play a crucial role in the pathogenesis of inflammatory diseases by mediating leukocyte migration from the blood into the tissue. Thus, the selectins and selectin ligands represent a promising therapeutic target for the treatment of COVID-19. In this paper, potential pan-selectin inhibitors were identified employing a virtual screening using a docking procedure. For this purpose, the Asinex and ZINC databases of ligands, including approved drugs, biogenic compounds, and glycomimetics, altogether 923 602 compounds, were screened against the P-, L-, and E-selectin. At first, the experimentally confirmed inhibitors were docked into all three selectins' carbohydrate recognition domains to assess the suitability of the screening procedure. Finally, based on the evaluation of ligands binding, we propose ten purchasable pan-selectin inhibitors to develop COVID-19 therapeutics.

show abstract

Strengthening an Intramolecular Non‐Classical Hydrogen Bond to Get in Shape for Binding

Varga,

Smieško,

Jiang

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

In this research article, we report on the strengthening of a non‐classical hydrogen bond (C‐H···O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E‐selectin ligand sialyl Lewisx (1, sLex). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre‐organization of sLex in its binding conformation. We have shown, that among the elements responsible for the pre‐organization, the stabilization by a non‐classical hydrogen bond between the H‐C5 of l‐fucose and the ring oxygen O5 of the neighboring d‐galactose moiety is essential and yields 7.4 kJ mol‐1. This effect could be further strengthened by replacing l‐fucose by 6,6,6‐trifluoro‐l‐fucose leading to an improved non‐classical H‐bond of 14.9 kJ mol‐1, i.e., an improved pre‐organization in the bioactive conformation. For a series of glycomimetics of sLex (1), this outcome could be confirmed by high field NMR‐shifts of the H‐C5Fuc, by X‐ray diffraction analysis of glycomimetics co‐crystallized with E‐selectin as well as by isothermal titration calorimetry. Furthermore, the electron‐withdrawing character of the CF3‐group beneficially influences the pharmacokinetic properties of sLex mimetics. Thus, acid‐stability a prerequisite for gastrointestinal stability could be substantially improved.

show abstract

Selectin antagonists and their potential impact for the treatment of inflammatory lung diseases

Cited by 4 publications

References 39 publications

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

Pan-selectin inhibitors as potential therapeutics for COVID-19 treatment: in silico screening study

Strengthening an Intramolecular Non‐Classical Hydrogen Bond to Get in Shape for Binding

Contact Info

Product

Resources

About