In recent years, many compounds having potent antiviral activity in cell culture have been detected and some of these compounds are currently undergoing either preclinical or clinical evaluation. Among these antiviral substances, naturally occurring sulfated polysaccharides and those from synthetic origin are noteworthy. Recently, several controversies over the molecular structures of sulfated polysaccharides, viral glycoproteins, and cell-surface receptors have been resolved, and many aspects of their antiviral activity have been elucidated. It has become clear that the antiviral properties of sulfated polysaccharides are not only a simple function of their charge density and chain length but also their detailed structural features. The in vivo efficacy of these compounds mostly corresponds to their ability to inhibit the attachment of the virion to the host cell surface although in some cases virucidal activity plays an additional role. This review summarizes experimental evidence indicating that sulfated polysaccharides might become increasingly important in drug development for the prevention of sexually transmitted diseases in the near future.

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Natural compounds offer interesting pharmacological perspectives for antiviral drug development. In this study, we have analysed sulphated-fucan-containing fractions isolated from the brown seaweed Cystoseira indica. The crude water extract (CiWE) and the main fraction (CiF3) obtained by anion exchange chromatography had potent antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) without cytotoxicity for Vero cell cultures. Furthermore, they had no direct inactivating effect on virions in a virucidal assay, and lacked anticoagulant activity. The mode of action of these compounds could be mainly ascribed to an inhibitory effect on virus adsorption. Chemical, chromatographic and spectroscopic methods showed that the major polysaccharide had an apparent molecular mass of 35 kDa and contained a backbone of alpha-(1 --> 3)-linked fucopyranosyl residues substituted at C-2 with fucopyranosyl and xylopyranosyl residues. This sulphated fucan, considered the active principle of the C. indica water extract, also contained variously linked xylose and galactose units and glucuronic acid residues. Sulphate groups, if present, are located mostly at C-4 of (1 --> 3)-linked fucopyranosyl units, and appeared to be very important for the anti-herpetic activity of this polymer.

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer-monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer-trimer equilibrium not reported for other TNF family members. This unique assembly behavior has direct implications for hGITRL-GITR signaling, because enforced trimerization of soluble hGITRL ectodomain results in an Ϸ100-fold increase in its receptor binding affinity and also in enhanced costimulatory activity. The apparent reduction in affinity that is the consequence of this dynamic equilibrium may represent a mechanism to realize the biologically optimal level of signaling through the hGITRL-GITR pathway, as opposed to the maximal achievable level.crystal structure ͉ T cell costimulation

SummaryCostimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor/ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review we highlight unique insights that have been revealed by structures of costimulatory molecules from the immunoglobulin and tumor necrosis factor superfamilies, and describe a vision for future structural and mechanistic analysis of costimulation. This vision includes simple strategies for the selection of candidate molecules for structure determination and highlights the critical role of structure in the design of mutant costimulatory molecules for the generation of in vivo structure-function correlations in a mammalian model system. This integrated 'atoms-to-animals' paradigm provides a comprehensive approach for defining atomic and molecular mechanisms.