1,721,251 research outputs found
Fully synthetic carbohydrate-based antibacterial vaccines
No full textAlthough the enormous progresses achieved by modern medicine, numerous diseases have still a profound impact on public health. Infectious diseases caused by a variety of microorganisms (viruses, fungi and parasites) and bacteria are a global major concern, not only in developing countries, due for instance to the emergence of multidrug resistance. The development of preventative therapies, such as the rational design of novel and more efficient vaccines, may offer a solution to this and other drawbacks. Vaccination is considered by the World Health Organization to be the most cost-effective strategy for controlling infectious disease, since it should confer long-term protective immunity in the population.Carbohydrates play a key role in many molecular recognition phenomena and they can affect any kind of interaction with the immune system. Therefore, saccharide-based antigens (for instance, bacterial capsular polysaccharides or tumor associated carbohydrate antigens) have been studied and employed in the formulation of vaccines. During last years, there has been a growing use of synthetic saccharide antigens for the formulation of vaccine candidates. These structures are indeed chemically well defined, devoid of biologic contaminants and, in principle, available in large amount, compared to material extracted from natural sources. In addition, synthetic saccharide antigens can also serve as haptens in protein conjugates, eliciting highly specific antibodies in animal models and humans
Synthesis of neisseria meningitidis x capsular polysaccharide fragments
No full textN. meningitidis type X (Men X), first described in the 1960s1, has been found to cause a few cases of invasive disease and in 2006 WHO started to consider Men X as a substantial threat, when an unprecedented incidence of meningitis caused by Men X was observed in Niger and in Western Kenya. The development of carbohydrate-based vaccines has recently emerged as a possible approach with enormous potential benefits for human health. Since capsular polysaccharides (CPSs) are the key virulence factors for encapsulated bacteria, the development of more comprehensive conjugate vaccines including Men X CPS fragments become an urgent issue in the near future.
The CPS of N. meningiditis X is a linear homopolymer of (14)-linked 2-acetamido-2-deoxy-alpha-D-glucopyranosyl phosphate residues, with an average chain length of 50 units.
The present research project is focused on the synthesis of phosphodiester-linked oligomers of the native Men X CPS. In order to improve the immune response of the synthesized oligomers they will be employed in the synthesis of neo-glycoconjugates by exploiting the amino group of the spacer arm at the reducing end of each fragment
Chemical contributions to understanding heparin activity: Synthesis of related sulfated oligosaccharides
No full textHeparin and heparan sulfate are complex polysaccharides that modulate several biological events through the recognition of a number of distinct proteins. Chemical synthesis is a powerful tool to identify the unique binding domains responsible for the specific interactions and to generate potent analogues of the natural sequences. The present review reports the synthetic efforts of the last decade that are focused on the preparation of tailored fragments of these two polymers and analogues thereof. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003
Exploring glycosylation reactions under continuous-flow conditions
Full text linkThe industrial development of carbohydrate-based drugs is greatly thwarted by the typical challenges inherent in oligosaccharide synthesis. The practical advantages of continuous-flow synthesis in microreactors (high reproducibility, easy scalability, and fast reaction optimization) may offer an effective support to make carbohydrates more attractive targets for drug-discovery processes. Here we report a systematic exploration of the glycosylation reaction carried out under microfluidic conditions. Trichloroacetimidates and thioglycosides have been investigated as glycosyl donors, using both primary and secondary acceptors. Each microfluidic glycosylation has been compared with the corresponding batch reaction, in order to highlight advantages and drawbacks of microreactors technology. As a significant example of multistep continuous-flow synthesis, we also describe the preparation of a trisaccharide by means of two consecutive glycosylations performed in interconnected microreactors
Synthesis of Neisseria meningitidis X capsular polysaccharide fragments
No full textSerotype X of Neisseria meningitidis bacterium (Men X) recently emerged as a substantial threat to public health. Since anti-meningococcal vaccines currently available or under investigation do not contain antigenic components of Men X capsular polysaccharide, there is the need to develop more comprehensive conjugate vaccines capable to offer higher protection. As a preliminary step towards this goal, the synthesis of three conjugatable Men X capsular polysaccharide fragments is described. The installation of the crucial α-glycosyl phosphodiester linkages is based on the hydrogenphosphonate methodology using pure α-glycosyl hydrogenphosphonates 10 and 12 obtained from hemiacetals 9 and 11, respectively
Exploring new methods to control the stereoselectivity of glycosylation reactions
No full textThe synthesis of complex carbohydrate remains a challenge for synthetic chemists, especially in terms of stereocontrol (anomeric ratio) of glycosylation reactions. The stereoselective formation of glycosidic bonds depends indeed on numerous factors such as the reaction temperature, the solvent, the reagents concentration, the promoter and the coupling partners. In addition, the monosaccharide residues required for the assembly of larger saccharide structures are precious synthetic intermediates themselves as they require multistep synthesis. Large amount of starting material are usually consumed for the identification of the best reaction conditions using traditional batch procedures, and their optimization and subsequent scale-up of the optimized reaction conditions pose an additional hurdle. Continous-flow microfluidic devices offer a well-engineered approach to meet some of these challenges, especially in terms of better control of reaction parameters.
Quite surprisingly, glycosylation reactions have been still little explored under continous-flow conditions, and only few example of this chemistry are reported in the literature.1
The aim of the present research project is to investigate the use of microfluidic reactor in carbohydrate chemistry area, with particular emphasis on the glycosylation reactions (especially in terms of stereoselection control). Initially, a panel of different glycosyl acceptors (primary and secondary) and different glycosyl donors (with or without neighbouring participating group at C-2 and with different leaving group at the anomeric carbon) were synthesized and employed in glycosylation reactions under batch conditions.
Then, some glycosylation reactions were carried out under microfluidic conditions in order to compare their relative efficiencies.
Stereochemical control of glycosylation reaction can be also achieved by using chiral promoter. Inspired by Fairbanks and co-workers who recently described glycosylation reactions promoted by a chiral Brønsted acid catalyst,2 we decided to explore the use of a chiral Lewis acid catalyst to induce stereoselective glycosylations. In particular, the stereochemical course of a model glycosylation reaction has been investigated using the trimethylsilyl esters derived from (R/S)-BINOL phosphoric acid
Synthesis of Fragment of beta-Glucans as Potential Ligands for Dectin-1
No full textBeta-glucans are glucose polymers linked together by a 1,3 linear beta-glycosidic chain core, differing from each other by their length and branching configuration. The branches derived from the glycosidic chain core are either 1,4 or 1,6 glycosidic chains and appear to be dependent on the source.
Dectin-1 is a unique C-type lectin that recognizes beta-glucan carbohydrates present on the surface of various fungi, including C. albicans. Its activation promotes microbial uptake and phagocytosis, but also mediates, in synergy with TLRs, the production of cytokines such as IL-12 and TNF alfa, leading ultimately to the initiation of the adaptive immune response. For this reason, beta-glucans – or their fragments – can be referred to as a possible class of adjuvants to increase the immune response to pathogens. In addition, the administration of beta-glucan-derived compounds can help in gaining new insights on the mechanism of action of dectin-1 receptor.
Dectin-1 binds beta-glucan polymers with affinities ranging from very low (3x10-3 M) to very high (2x10-12 M). The wide range of affinities appears to be due to the differing sizes and numbers of branches in -glucans from various sources.
Although the interaction between Dectin-1 and beta-glucans has been supposed to involve a conformational epitope as a high order local helix, little is known about the binding mode and the degree of (1-6)-branching of the glucan chain in the binding epitope. For this reason, a series of fragments of beta-glucans, differing in the 6-O branching degree, has been synthesised. Their ability to bind to dectin-1 and of activating the inflammatory response will be subsequently tested
Gold nanoparticle-based platforms for vaccine development
Full text linkSince their discovery, therapeutic or prophylactic vaccines
represent a promising option to prevent or cure
infections and other pathologies, such as cancer or
autoimmune disorders. More recently, among a number
of nanomaterials, gold nanoparticles (AuNPs) have
emerged as novel tools for vaccine developments,
thanks to their inherent ability to tune and upregulate
immune response. Moreover, owing to their features,
AuNPs can exert optimal actions both as delivery
systems and as adjuvants. Notwithstanding the potential
huge impact in vaccinology, some challenges remain
before AuNPs in vaccine formulations can be
translated into the clinic. The current review provides
an updated overview of the most recent and effective
application of gold nanoparticles as efficient means to
develop a new generation of vaccine
Synthesis of Lewis A and Lewis X pentasaccharides based on N-trichloroethoxycarbonyl protection
No full textThexyldimethylsilyl 4,6-O-benzylidene-2-deoxy-2-trichloroethoxycarbonylamino-beta-D-glucopyranoside (4), having the 3-hydroxy group unprotected, is a versatile starting material for the synthesis of glucosamine containing oligosaccharides. Thus, reaction with galactosyl donor 5 or fucosyl donor 6 afforded the desired beta(1-3)- and alpha(1-3)-linked disaccharides 7 and 8, respectively, in high yields, Reductive opening of the benzylidene moieties in 7 and 8 gave access to the 4-hydroxy groups in 9 and 10. Ensuing fucosylation of 9 or galactosylation of 10 led to Lewis A (Le(a)) and Lewis X (Le(x)) trisaccharide building blocks 13 and 14, respectively. Their transformation into glycosyl donors 19 and 20 and subsequent reaction with 3b-O-unprotected lactose derivative 23 as acceptor furnished the Le(a)- and Le(x) pentasaccharide precursors 24 and 25. Exchange of the N-trichloroethoxycarbonyl group for an N-acetyl group and removal of the O-benzyl and O-acetyl protective groups afforded the desired Le(a)- and Lex-pentasaccharides 1 and 2
Carbohydrates and Immunology : Synthetic Oligosaccharide Antigens for Vaccine Formulation
No full textDespite the enormous progress achieved by modern medicine,
numerous diseases still have a profound impact on public
health. Infectious diseases caused by a variety of microorganisms
(viruses, fungi and parasites) and bacteria are a
global major concern and, because of the emergence, for instance,
of multidrug resistance, not only in developing countries.
The development of preventative therapies, such as the
rational design of novel and more efficient vaccines, might
offer a solution to this state of affairs and other associated
drawbacks. Vaccination is considered by the World Health
Organization to be the most cost-effective strategy for controlling
infectious disease, because it should confer long-term
protective immunity in the population. A second consideration
involves cancer. The outstanding progress achieved in
the identification and structural characterization of tumourassociated
antigens has prompted their employment in tumour
immunotherapy, on the basis of the observation that
tumour cells possess specific antigens that can be recognized
by an immune system appropriately conditioned to the task. Carbohydrates play key roles in many molecular recognition
phenomena and they can affect any kind of interaction with
the immune system. Saccharide-based antigens (bacterial
capsular polysaccharides or tumour-associated carbohydrate
antigens, for instance) have therefore been studied and employed
in the formulation of vaccines. In recent years there
has been increasing use of synthetic saccharide antigens for
the formulation of vaccine candidates. These structures are
indeed chemically well defined, devoid of biologic contaminants
and, in principle, available in large amounts, relative
to materials extracted from natural sources. In addition, synthetic
saccharide antigens can also serve as haptens in protein
conjugates, eliciting highly specific antibodies in animal
models and humans. The great potential of synthetic saccharide
antigens is attested to by the spectacular success of the
Cuban vaccine against Haemophilus influenzae type b. Here
we review the major advances in the development of synthetic
carbohydrate-based vaccines targeted against infectious
diseases and cancer
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