Dataset Information

Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

ABSTRACT: Hyaluronan (HA) plays important roles in a wide range of biological events. The principal receptor of HA in the human body is the Cluster of Differentiation 44 (CD44). To enhance the binding between HA and CD44, a new approach was designed to take advantage of the four-component Ugi reaction. By modifying the carboxyl group on HA with various amine, aldehyde, and isocyanide moieties through the Ugi reaction, 36 HA like polysaccharides were generated. Two lead compounds were identified with enhanced CD44 binding compared to unmodified HA, which was confirmed by surface plasmon resonance (SPR), cellular studies and an in vivo mouse tumor model. Ski-learn as a machine learning tool was applied to analyze library data and yield predictions with an accuracy over 80 %. In conclusion, modification of HA via the Ugi reaction can be a promising strategy to develop novel binders toward HA receptors such as CD44.

SUBMITTER: Liu K

PROVIDER: S-EPMC10322327 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

Liu Kunli K McCue William M WM Yang Chia-Wei CW Finzel Barry C BC Huang Xuefei X

Carbohydrate polymers 20221025

Hyaluronan (HA) plays important roles in a wide range of biological events. The principal receptor of HA in the human body is the Cluster of Differentiation 44 (CD44). To enhance the binding between HA and CD44, a new approach was designed to take advantage of the four-component Ugi reaction. By modifying the carboxyl group on HA with various amine, aldehyde, and isocyanide moieties through the Ugi reaction, 36 HA like polysaccharides were generated. Two lead compounds were identified with enhan ...[more]

PMID: 36372512

Similar Datasets

Project description:We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH. HMWH also reverses the hyperalgesia induced by diverse pronociceptive mediators, prostaglandin E2, epinephrine, TNFα, and interleukin-6, and the neuropathic pain induced by the cancer chemotherapy paclitaxel. Although CD44 antisense has no effect on the hyperalgesia induced by inflammatory mediators or paclitaxel, it eliminates the antihyperalgesic effect of HMWH. HMWH also reverses the hyperalgesia induced by activation of intracellular second messengers, PKA and PKCε, indicating that HMWH-induced antihyperalgesia, although dependent on CD44, is mediated by an intracellular signaling pathway rather than as a competitive receptor antagonist. Sensitization of cultured small-diameter DRG neurons by prostaglandin E2 is also prevented and reversed by HMWH. These results demonstrate the central role of CD44 signaling in HMWH-induced antihyperalgesia, and establish it as a therapeutic target against inflammatory and neuropathic pain.SIGNIFICANCE STATEMENT We demonstrate that hyaluronan (HA) with different molecular weights produces opposing nociceptive effects. While low molecular weight HA increases sensitivity to mechanical stimulation, high molecular weight HA reduces sensitization, attenuating inflammatory and neuropathic hyperalgesia. Both pronociceptive and antinociceptive effects of HA are mediated by activation of signaling pathways downstream CD44, the cognate HA receptor, in nociceptors. These results contribute to our understanding of the role of the extracellular matrix in pain, and indicate CD44 as a potential therapeutic target to alleviate inflammatory and neuropathic pain.

Dataset Information

Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

Publications

Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets