Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery.
Heparin is a sulphated glycosaminoglycan currently used as an anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated IdoA not l&r arrow N, 6-O-disulphated GlcN disaccharide units. Other disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated GlcN are also present as minor components. This heterogeneity is more pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are the most abundant. Heparin/HS bind to a variety of biologically active polypeptides, including enzymes, growth factors and cytokines, and viral proteins. This capacity can be exploited to design multi-target heparin/HS-derived drugs for pharmacological interventions in a variety of pathologic conditions besides coagulation and thrombosis, including neoplasia and viral infection. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor N-acetyl heparosan. The possibility of producing K5 polysaccharide derivatives by chemical and enzymatic modifications, thus generating heparin/HS-like compounds, has been demonstrated. These K5 polysaccharide derivatives are endowed with different biological properties, including anticoagulant/antithrombotic, antineoplastic, and anti-AIDS activities. Here, the literature data are discussed and the possible therapeutic implications for this novel class of multi-target "biotechnological heparin/HS" molecules are outlined.
Rusnati
Marco
M
Unit of General Pathology & Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy.
Oreste
Pasqua
P
Zoppetti
Giorgio
G
Presta
Marco
M
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D016667:Bacterial Capsules; D006493:Heparin / Q000096:biosynthesis* / Q000627:therapeutic use; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis / Q000627:therapeutic use; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control
D000925:Anticoagulants; D006493:Heparin; D006497:Heparan Sulfate; D011135:Polysaccharides, Bacterial; C050673:capsular polysaccharide K5