Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans, has numerous important biological activities, associated with its interaction with diverse proteins. Heparin is widely used as an anticoagulant drug based on its ability to accelerate the rate at which antithrombin inhibits serine proteases in the blood coagulation cascade. Heparin and the structurally related heparan sulfate are complex linear polymers comprised of a mixture of chains of different length, having variable sequences. Heparan sulfate is ubiquitously distributed on the surfaces of animal cells and in the extracellular matrix. It also mediates various physiologic and pathophysiologic processes. Difficulties in evaluating the role of heparin and heparan sulfate in vivo may be partly ascribed to ignorance of the detailed structure and sequence of these polysaccharides. In addition, the understanding of carbohydrate–protein interactions has lagged behind that of the more thoroughly studied protein–protein and protein–nucleic acid interactions. The recent extensive studies on the structural, kinetic, and thermodynamic aspects of the protein binding of heparin and heparan sulfate have led to an improved understanding of heparin–protein interactions. A high degree of specificity could be identified in many of these interactions. An understanding of these interactions at the molecular level is of fundamental importance in the design of new highly specific therapeutic agents. This review focuses on aspects of heparin structure and conformation, which are important for its interactions with proteins. It also describes the interaction of heparin and heparan sulfate with selected families of heparin‐binding proteins.

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1alpha (HIF1-alpha); overexpression of HIF1-alpha is correlated with increased tumour invasiveness and resistance to chemotherapy. Here we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an 'integrative' approach in cancer therapy.

Heparin, ein zu den Glycosaminoglycanen gehörendes sulfatiertes Polysaccharid, zeigt eine Reihe wichtiger biologischer Wirkungen, die aus der Wechselwirkung mit Proteinen resultieren. Da Heparin die Geschwindigkeit erhöht, mit der Antithrombin die Serinproteasen in der Blutgerinnungskaskade inhibiert, findet es breite Anwendung als Antikoagulans (Antiblutgerinnungsmittel). Heparin und das strukturverwandte Heparansulfat sind komplizierte lineare Polymere, die aus Ketten unterschiedlicher Länge und Sequenz bestehen. Heparansulfat, das an den Oberflächen tierischer Zellen und in der extrazellulären Matrix ubiquitär ist, vermittelt ebenfalls eine Reihe physiologischer und pathophysiologischer Prozesse. Die Schwierigkeiten bei der Beurteilung der Rolle von Heparin und Heparansulfat in vivo können zum Teil auf die Unkenntnis der genauen Struktur und Sequenz dieser Polysaccharide zurückgeführt werden. Abgesehen davon weiß man über Kohlenhydrat‐Protein‐Wechselwirkungen viel weniger als über die eingehend untersuchten Protein‐Protein‐ und Protein‐Nucleinsäure‐Wechselwirkungen. Die neuere umfangreiche Forschung über strukturelle, kinetische und thermodynamische Aspekte der Proteinbindung von Heparin und Heparansulfat führte zu neuen Erkenntnissen über die Heparin‐Protein‐Wechselwirkungen. Viele dieser Wechselwirkungen sind hochspezifisch, deshalb ist es für die Entwicklung neuer Therapeutika von grundlegender Bedeutung, sie auf molekularer Ebene zu verstehen. Dieser Aufsatz konzentriert sich auf die strukturellen und konformativen Eigenschaften von Heparin, die für die Wechselwirkungen mit Proteinen wichtig sind, außerdem wird die Wechselwirkung von Heparin und Heparansulfat mit ausgewählten Heparin‐bindenden Proteingruppen behandelt.

Heparin has been used clinically as an anticoagulant for over 60 years. Typically isolated from porcine intestine, heparin is a mixture of dimeric glycosidic sequences generating complex polysaccharide glycosaminoglycan chains. Recently, certain lots of heparin have been associated with an acute, rapid onset of significant side effects indicative of an allergic-type reaction. To identify potential causes for this serious rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high resolution analytical techniques. Through comparison of these results with those obtained on reference lots, suspect lots were found to contain a highly sulfated chondroitin sulfate contaminant. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked β1→3 to a β-galactosamine. Surprisingly, the disaccharide unit contains an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. The presence of such a contaminant could elicit a biological response as highly sulfated polysaccharides, such as dextran sulfate, are known to be potent mediators of the immune system. Given the nature of the contaminant, traditional screening tests -such as those present as part of the current United States Pharmacopeia heparin monograph -cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be employed to determine whether or not heparin lots contain the contaminants reported here.

Adjuvanted vaccines afford invaluable protection against disease, and the molecular and cellular changes they induce offer direct insight into human immunobiology. Here we show that within 24 h of receiving adjuvanted swine flu vaccine, healthy individuals made expansive, complex molecular and cellular responses that included overt lymphoid as well as myeloid contributions. Unexpectedly, this early response was subtly but significantly different in people older than ∼35 years. Wide-ranging adverse clinical events can seriously confound vaccine adoption, but whether there are immunological correlates of these is unknown. Here we identify a molecular signature of adverse events that was commonly associated with an existing B cell phenotype. Thus immunophenotypic variation among healthy humans may be manifest in complex pathophysiological responses.