Glycomimetics for the inhibition and modulation of lectins

Leusmann, Steffen; Ménová, Petra; Shanin, Elena; Titz, Alexander; Rademacher, Christoph

doi:10.1039/d2cs00954d

Cited by 45 publications

(29 citation statements)

References 689 publications

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“…[1] In this framework, a vibrant and dynamic area of research concerns approaches that target lectins. [6,7] To mention some, a small molecule E-selectin [8] inhibitor, Uproleselan, is undergoing late-stage clinical trials. [9] It works by disrupting E-selectin/sLe X interaction and it results in a significant antitumor activity, and in an increased chemosensitivity in patients with relapsed or refractory acute myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc Trisaccharide: a new Ligand for DCAR and Mincle C‐Type Lectin Receptors

Tricomi,

Aoun,

et al. 2024

ChemBioChem

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In this work, we have discovered that the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc trisaccharide, a fragment of the B antigen Type‐1, is a new ligand of two C‐type lectin receptors (CLRs) i.e. DCAR and Mincle which are key players in different types of autoimmune diseases. Accordingly, we report here on a straightforward methodology to access pure Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc trisaccharide. A spacer with a terminal primary amine group was included to the reducing end of the GlcNAc residue thus ensuring the further functionalization of the trisaccharide Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc

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Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc Trisaccharide: a new Ligand for DCAR and Mincle C‐Type Lectin Receptors

Tricomi,

Aoun,

et al. 2024

ChemBioChem

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“…Meanwhile, small molecules (e.g., molecular glue and PROTAC) also have many of the same point mutational resistance liabilities of TKIs. Other approaches used for surface and extracellular soluble targets (e.g., LYTAC, ATAC, KineTAC) (14)(15)(16) engage surface protein trafficking systems. Often targeting membrane sugar receptors (cation-independent mannose-6-phosphate receptor [CI-M6PR] or asialoglycoprotein receptor [ASGPR]) but also cytokine receptors (e.g., CXCR7), these are designed to "hitch a ride" with the uptake receptor into the cell before target release in the endolysosomal system.…”

Section: Introductionmentioning

confidence: 99%

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

Crook,

Sevilla,

Young

et al. 2024

Preprint

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Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell’s protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYticpH-dependentEndolysosomal delivery withRecycling) technology with potency and durability from a novel catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal target delivery while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstratedin vitrowith EGFR and PD-L1, andin vivowith EGFR in a model of EGFR-driven non-small cell lung cancer.

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“…All these studies reveal a crucial role of Gal-1 produced by tumor stromal cells in cancer progression. Indeed, Gal-1 has been considered an interesting therapeutic target in cancer [ 172 ].…”

Section: Introductionmentioning

confidence: 99%

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis

Perez-Moreno,

Oyanadel,

de la Peña

et al. 2024

Biol Res

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Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

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Glycomimetics for the inhibition and modulation of lectins

Abstract: Carbohydrates are essential mediators of many processes in health and disease. The development of glycomimetics as inhibitors and modulators of their lectin receptors has been a success story with numerous molecules reaching clinical stages.

Cited by 45 publications

References 689 publications

Stereoselective Synthesis of the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc Trisaccharide: a new Ligand for DCAR and Mincle C‐Type Lectin Receptors

Stereoselective Synthesis of the Gal‐α‐(1→3)‐Gal‐β‐(1→3)‐GlcNAc Trisaccharide: a new Ligand for DCAR and Mincle C‐Type Lectin Receptors

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis

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