Biotechnological Engineering of Heparin/Heparan Sulphate: A Novel Area of Multi-Target Drug Discovery

Abstract

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.

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

“…In conclusion, K5-NSOS is a potential antimetastatic and antiresorptive agent with low anticoagulant activity. Additional modification of the size and sulfation degree of K5-NSOS could further lower its anticoagulant activity (7,37) and improve its applicability as a therapeutic agent to prevent and treat breast cancer metastases.…”

BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

“…In this scenario, the basic domain/NLS of Tat emerges as a preferential molecular target, being involved in several intra-and extracellular actions of Tat. In effect, the basic domain of Tat has been exploited to develop polyanionic compounds, mainly studied for their potential as extracellular Tat-antagonists (Rusnati and Presta, 2002b;Rusnati et al, 2005) or microbicides . Unfortunately, these compounds usually lack specificity and cell permeability and suffer from high toxicity and anticoagulant activity (Urbinati et al, 2008).…”

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…They include, among others, polysulfated/polysulfonated compounds and biotechnological heparins (see Ref. [121] for a comprehensive review about this point). Since heparin binds a variety of angiogenic/mitogenic growth factors besides FGFs [122], heparin-like drugs might have the advantage to sequester various growth factors simultaneously, acting as "multitarget" inhibitors [123].…”