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.

Atomistic fingerprint of hyaluronan–CD44 binding

“…In particular, our work shows why and how R41 is crucial in the recognition of HA in all the three binding modes of which one was detected previously by crystallography [ 10 ] and two were observed for the first time in our simulations. Our results expand the molecular-scale knowledge of the CD44–HA interplay and therefore have potential to facilitate the development of novel therapies against conditions such as the metastasis of tumors [ 32 , 33 ].…”

Hyaluronan as a therapeutic target in human diseases

“…An intralymphatic drug delivery method using an HA-cisplatin conjugate was proposed in breast cancer to preferentially treat at-risk regional lymph nodes and avoid systemic toxicities [267]. Furthermore, HA-based nanocarriers were investigated as drug vehicles for systemic targeting of CD44-overexpressed cancers [268, 269]. HA-coated superparamagnetic iron oxide nanoparticles conjugated anticancer drug doxorubicin was delivered at much higher levels and distributed wider in the tumor tissue than intravenously injected free doxorubicin, leading to significant reduction of tumor growth [270].…”

Chemical modification of hyaluronan oligosaccharides differentially modulates hyaluronan- hyaladherin interactions

“…The increases in affinity seen here for the aminobenzoic acid-modified tetrasaccharides were similar to the findings of Lu and Huang (67), whose lead compound was a modified thiol glycoside attached to the closed reducing terminal ring of HA4 AN . In silico modeling (67) suggested that the m-benzyl phenyl moiety of the compound could fit into the hydrophobic pocket (consisting of Cys81, Tyr83, Ile92 and Cys101), within the HA binding groove of CD44 (31,67), π-π stacking against the tyrosine sidechain. Thus, the aromatic rings of the aminobenzoic acid moieties studied here could be involved in similar stacking interactions within this pocket, resulting in the improved affinities observed (see Figure 1).…”