Dataset Information

Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.

ABSTRACT: Hyaluronan (HA) is an integral component of the extracellular matrix. Its interactions with a cell surface receptor CD44 has been shown to play important roles in a variety of biological events including cell proliferation and metastasis. As multivalent CD44-HA binding is critical for downstream signaling, compounds that can selectively disrupt the complex formation of HA polysaccharide with CD44 can serve as useful probes of CD44 mediated cellular events as well as potential leads for novel therapeutics. Herein, we report the synthesis of several series of HA conjugates to target the HA binding pocket of CD44. As a small library of HA disaccharide derivatives failed to exhibit any inhibitory activities, we focused on HA tetrasaccharide based analogs. Traditional synthetic strategies towards HA oligosaccharides involve the construction of backbone from the corresponding monosaccharide building blocks, which can be quite tedious. In order to expedite the synthesis, we designed a new synthetic route taking advantage of the ability of hyaluronidase to generate large quantities of HA tetrasaccharide through digestion of HA polysaccharides. The HA tetrasaccharide obtained was utilized to prepare multiple S-linked HA analogs bearing aromatic groups at the reducing end glycan. One such compound containing an m-benzyl phenyl moiety exhibited significant inhibition of CD44-HA binding. Our approach provides a new direction towards the design of HA based CD44 antagonists.

SUBMITTER: Lu X

PROVIDER: S-EPMC4712157 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.

Lu Xiaowei X Huang Xuefei X

Glycoconjugate journal 20150522 7

Hyaluronan (HA) is an integral component of the extracellular matrix. Its interactions with a cell surface receptor CD44 has been shown to play important roles in a variety of biological events including cell proliferation and metastasis. As multivalent CD44-HA binding is critical for downstream signaling, compounds that can selectively disrupt the complex formation of HA polysaccharide with CD44 can serve as useful probes of CD44 mediated cellular events as well as potential leads for novel the ...[more]

PMID: 25997408

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

Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.

Publications

Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets