These new constructs include also fully synthetic vaccines exploiting the multivalency effect, where a significant enhancement of the immunogenicity is achieved by display of multiple copies of the oligosaccharide antigen on a suitable polyfunctional scaffold

These new constructs include also fully synthetic vaccines exploiting the multivalency effect, where a significant enhancement of the immunogenicity is achieved by display of multiple copies of the oligosaccharide antigen on a suitable polyfunctional scaffold. the carbohydrate antigen from its natural resource often lead to poor homogeneity and presence of biological pollutants, resulting in batch-to-batch variability. Moreover, in some cases, the mind-boggling immunogenicity of the carrier protein may induce the carbohydrate epitope suppression, causing hyporesponsiveness. The development of synthetic oligosaccharide-based vaccine candidates, characterized by the presence of genuine and well-defined synthetic oligosaccharide constructions, is definitely expected to fulfill the requirement of homogeneous and highly reproducible preparations. In the present chapter, we statement on the major advances in the development of synthetic carbohydrate-based vaccines. First of all, we describe different strategies formulated during the last years to circumvent the inherent difficulties of classical oligosaccharide synthesis, such as the one-pot glycosylation and the solid-phase synthesis, and their software to the preparation of carbohydrate antigens apt to conjugation with protein service providers. Next, we discuss probably the most representative methodologies employed for the chemical ligation of oligosaccharide constructions to proteins. Finally, in the last section, we statement significant examples of fully synthetic vaccines exploiting the multivalency effect. These constructs are based on the concept the conjugation of multiple copies of synthetic oligosaccharide antigens to multivalent scaffolds, such as dendrimers, (cyclo)peptides, platinum nanoparticles, and calixarenes, increases cooperative relationships between carbohydrates and immune receptors, leading to strong enhancement of the saccharide Mouse monoclonal to CD38.TB2 reacts with CD38 antigen, a 45 kDa integral membrane glycoprotein expressed on all pre-B cells, plasma cells, thymocytes, activated T cells, NK cells, monocyte/macrophages and dentritic cells. CD38 antigen is expressed 90% of CD34+ cells, but not on pluripotent stem cells. Coexpression of CD38 + and CD34+ indicates lineage commitment of those cells. CD38 antigen acts as an ectoenzyme capable of catalysing multipe reactions and play role on regulator of cell activation and proleferation depending on cellular enviroment antigen immunogenicity. type b (Verez-Bencomo et al. 2004). Olodaterol Synthetic carbohydrate antigens have, indeed, defined composition, and they can be produced as homogeneous compounds in a controlled manner with little or no batch-to-batch variability, affording highly reproducible biological properties. In addition, some microorganisms communicate carbohydrate constructions that have close similarity to mammalian tissue-specific constructions, and this molecular mimicry may induce tolerance from the hosts immune system. One approach to evade this immune tolerance is to use a chemically revised version of the carbohydrate, an option available only with the recourse to the chemical synthesis. The unnatural structure will become perceived as a foreign antigen from the sponsor, but at the same time, it should elicit antibodies able to cross-react with the natural glycan expressed within the pathogen cell surface. On the basis of these considerations, the present chapter deals with the major improvements in the formulation of synthetic carbohydrate-based vaccines, with a particular focus on the strategies and relevant synthetic methodologies that emerged during the last years. First and foremost, for the sake of clarity and with the purpose to facilitate the comprehension of the material by nonspecialized Olodaterol readers, we statement a glossary defining the most significant terms referred to the complex machinery of the immune response and used throughout this chapter. The following section highlights the most significant synthetic methodologies applied to the preparation of carbohydrate-based vaccine candidates. Finally, the new strategies (or fresh applications of the existing ones) carried out for the design of fresh, more efficient, and safer vaccines based on the conjugation of synthetic oligosaccharides with protein service providers and polyfunctional scaffolds (in order to exploit the multivalency effect) are explained and critically discussed. It should Olodaterol be mentioned that a comprehensive review focused on the preparation of vaccines or vaccine candidates based on fully synthetic carbohydrate antigens but classified according to the target disease (infections from bacteria, viruses, parasites, fungi, and malignancy) has been published by our group in 2011 (Morelli et al. 2011). New Methodologies for the Synthesis of Oligosaccharides as Vaccine Candidates Due to the enormous importance of carbohydrates in different biological processes (Varki et al. 2009; Dwek 1996; Varki 1993), the study of their functions and structure-activity human relationships (SARs) needs homogeneous and well-defined oligosaccharides. As stated above, the achievement of carbohydrate constructions in high purity and amount from natural sources is definitely a tough and complex process. To overcome these problems, significant efforts have been carried out for the development of chemical and enzymatic synthesis of well-defined oligosaccharides and conjugates (Zhu and Schmidt 2009; Boltje et al. 2009; Fraser-Reid et al. 2008; Kamerling 2007; Wong 2003; Ernst et al. 2000; Nicolaou and Mitchell 2001; Koeller and Wong 2001; Seeberger and Werz 2007; Bertozzi and Kiessling 2001). The synthesis of carbohydrates is more difficult than the synthesis of the additional two major classes of biopolymers (peptides/proteins and nucleotides/DNA and RNA). In the building of oligosaccharides, two major challenges have to be taken into consideration: the regioselective safety/deprotection of polyhydroxy organizations and the stereoselective formation of glycosidic linkages. The chemical synthesis of oligosaccharides requires monosaccharide building blocks with appropriate protecting organizations and anomeric leaving group. The mammalian glycome includes a limited quantity Olodaterol of monosaccharides and linkages, so using only a limited quantity of building blocks, a large variety of oligosaccharides could be prepared by a proven synthetic strategy (Werz et al. 2007a). This will also be true.