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Design, Synthesis, and Applications of Galectin Modulators in Human Health

  • Alison Mackinnon
  • Wei-Sheng Chen
  • Hakon Leffler
  • Noorjahan Panjwani
  • Hans Schambye
  • Tariq Sethi
  • Ulf J. Nilsson
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 12)

Abstract

Over the last decade, the family of galectin proteins has been identified as key regulators of important biological processes. They bind β- d-galactopyranoside residues in glycoconjugates, and by presenting multiple binding sites, within one galectin or by forming dimers or multimers, they can cross-link glycoproteins and form galectin-glycoprotein lattices. Such lattices formed on the cell surface or in vesicles have been shown to control, for example, surface residence time and signaling by receptors. Hence, compounds modulating galectin binding to their glycoprotein ligands are of potential clinical interest. This chapter describes the design and development of disubstituted thiodigalactoside derivatives that form optimal interactions with the galectin-3 binding site resulting in double-digit nanomolar affinities. Studies are discussed in which such galectin-3-modulating compounds have been important in elucidating galectin-3 mechanisms, including galectin-3 trafficking, cancer, inflammation, fibrosis, and angiogenesis. Medically relevant models using the galectin-3 modulators in characterizing macrophage alternative activation and chronic inflammation, myofibroblast activation and fibrosis, and ocular angiogenesis are discussed in more detail. In summary, the high galectin-3 affinity and definitive effects in relevant models of the disubstituted thiodigalactosides identify them as promising as lead compounds for drug development, albeit leaving a challenge in terms of optimizing PK/ADME properties.

Keywords

Angiogenesis Cancer CD98 Fibrosis Galectin Macrophage Modulator Myofibroblast Small molecule TGF-β VEGF 

Abbreviations

ADME

Absorption-distribution-metabolism-excretion

ApoE

Apolipoprotein E

bFGF

Basic fibroblast growth factor

CD31

Cluster of differentiation 31 protein

CD8

Cluster of differentiation 8 protein

CD98

Cluster of differentiation 98 protein

CRD

Carbohydrate recognition domain

DMSO

Dimethylsulfoxide

EGF

Epidermal growth factor

EGF-R

Epidermal growth factor receptor

EMT

Epithelial–mesenchymal transition

FDA

Food and Drug Administration

galectin-3C

Galectin-3 C-terminal domain

galectin-8N

Galectin-8 N-terminal domain

galectin-9N

Galectin-9 N-terminal domain

Grb2

Growth factor receptor-bound protein 2

I.T.

Intratracheal

IL4

Interleukin 4

IPF

Idiopathic pulmonary fibrosis

IRS-1

Insulin receptor substrate-1

JAK

Janus kinase

Kd

Dissociation constant

LacNAc

N-acetyllactosamine

Mgat5

β1,6-N-acetylglucosaminyl transferase 5

MHC-1

Major histocompatibility complex 1

MMFFs

Merck molecular force field s

PBS

Phosphate buffer saline

PDB

Protein data bank

PI3K

Phosphatidylinositide 3-kinase

PK

Pharmacokinetic

siRNA

Small interfering ribonucleic acid

Smad2

Mothers against decapentaplegic homolog 2

Smad3

Mothers against decapentaplegic homolog 3

STAT6

Signal transducer and activator of transcription 6

TCR

T-cell receptor

TGF-β

Transforming growth factor β

TGF-βRII

Transforming growth factor β receptor 2

Th2

Type 2 helper T cell

VEGF

Vascular epithelial growth factor

VEGF-R

Vascular epithelial growth factor receptor

VEGF-RII

Vascular epithelial growth factor receptor 2

WT

Wild type

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Alison Mackinnon
    • 1
  • Wei-Sheng Chen
    • 2
  • Hakon Leffler
    • 3
  • Noorjahan Panjwani
    • 2
    • 4
  • Hans Schambye
    • 5
  • Tariq Sethi
    • 6
  • Ulf J. Nilsson
    • 7
  1. 1.MRC Centre for Inflammation Research, The Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK
  2. 2.Sackler School of Graduate Biomedical SciencesTufts UniversityBostonUSA
  3. 3.Section MIG (Microbiology, Immunology, Glycobiology), Department of Laboratory MedicineLund UniversityLundSweden
  4. 4.Department of Ophthalmology, New England Eye CenterTufts UniversityBostonUSA
  5. 5.Galecto Biotech AB, CobisCopenhagen, NDenmark
  6. 6.Department of Respiratory Medicine and AllergyKings CollegeLondonUK
  7. 7.Department of Chemistry, Centre for Analysis and SynthesisLund UniversityLundSweden

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