Small-Molecule-Induced Clustering of Heparan Sulfate Promotes Cell Adhesion

• Published in: Journal of the American Chemical Society Vol. 135; no. 30; pp. 11032 - 11039
• Main Authors: Takemoto, Naohiro, Suehara, Tetsuya, Frisco, Heidie L, Sato, Shin-ichi, Sezaki, Takuhito, Kusamori, Kosuke, Kawazoe, Yoshinori, Park, Sun Min, Yamazoe, Sayumi, Mizuhata, Yoshiyuki, Inoue, Rintaro, Miller, Gavin J, Hansen, Steen U, Jayson, Gordon C, Gardiner, John M, Kanaya, Toshiji, Tokitoh, Norihiro, Ueda, Kazumitsu, Takakura, Yoshinobu, Kioka, Noriyuki, Nishikawa, Makiya, Uesugi, Motonari
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 31.07.2013; Amer Chemical Soc
• Subjects: Animals; Cell Adhesion - drug effects; Cell Line, Tumor; Chemistry; Chemistry, Multidisciplinary; Dimerization; Drug Design; Heparitin Sulfate - metabolism; Humans; Male; Mice; Models, Molecular; Physical Sciences; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Protein Multimerization - drug effects; Protein Structure, Quaternary; Science & Technology; Structure-Activity Relationship; Syndecans - chemistry; ACRIDINE-ORANGE; STEM-CELLS; CONSTRAINED PEPTIDE DIMERS; SYNDECAN-4; SPECTROSCOPIC PROPERTIES; CYTOSKELETAL ORGANIZATION; SEQUENCE; SYNTHETIC PEPTIDE; SELECTIVE DNA-BINDING; DIMERIZATION DOMAINS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4018682

Adhesamine is an organic small molecule that promotes adhesion and growth of cultured human cells by binding selectively to heparan sulfate on the cell surface. The present study combined chemical, physicochemical, and cell biological experiments, using adhesamine and its analogues, to examine the mechanism by which this dumbbell-shaped, non-peptidic molecule induces physiologically relevant cell adhesion. The results suggest that multiple adhesamine molecules cooperatively bind to heparan sulfate and induce its assembly, promoting clustering of heparan sulfate-bound syndecan-4 on the cell surface. A pilot study showed that adhesamine improved the viability and attachment of transplanted cells in mice. Further studies of adhesamine and other small molecules could lead to the design of assembly-inducing molecules for use in cell biology and cell therapy.