Carbohydrate-based synthetic vaccines: does the synthesis of longer chains of carbohydrates make this a step ever closer?
2012; Future Science Ltd; Volume: 4; Issue: 14 Linguagem: Inglês
10.4155/fmc.12.102
ISSN1756-8927
Autores Tópico(s)Infant Nutrition and Health
ResumoFuture Medicinal ChemistryVol. 4, No. 14 EditorialFree AccessCarbohydrate-based synthetic vaccines: does the synthesis of longer chains of carbohydrates make this a step ever closer?Kuo-Ching Chu & Chung-Yi WuKuo-Ching ChuGenomics Research Center, Academia Sinica, Taipei, Taiwan. & Chung-Yi Wu* Author for correspondenceGenomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan. Published Online:9 Oct 2012https://doi.org/10.4155/fmc.12.102AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: chemical synthesisconjugate vaccineoligosaccharidepolysaccharide vaccinesynthetic vaccineThe unique carbohydrate structures on the surfaces of invasive pathogens and the aberrant glycosylation on malignant cells make such carbohydrate moieties attractive immunotherapy targets. Currently, several kinds of oligosaccharide-based antibacterial vaccine are commercially available, and many clinical trials of promising vaccine candidates against human infectious diseases and various types of cancers are proceeding [1–3]. The commercially available carbohydrate–based antibacterial vaccines can be divided into two types: 'oligosaccharide vaccines', which contain only carbohydrates as immunogens; and 'conjugate vaccines', which consist of chemically conjugated carbohydrate antigens and immunogenic proteins. Because polysaccharides are usually T-cell-independent antigens that are unable to elicit a T-cell-assisted immune response, the 'oligosaccharide vaccines' usually elicit short-lasting antibody unless using zwitterionic oligosaccharides and cannot provide adequate protections for high-risk groups, such as infants and children under two years old. On the other hand, 'conjugate vaccines' usually elicit long-lasting antibodies and can provide adequate protections for the whole population [4].To date, the polysaccharides used in commercial vaccine production are derived from bacteria via large-scale pathogens culture, digestion, hydrolysis and then chromatography, to remove low-molecular weight, less immunogenic portion to obtain the well-accepted dogma, the protective B-cell epitopes, that is, 10–20 units of monosaccharide residues as the carbohydrate antigens source [5]. Although the vaccines constructed from isolating carbohydrate antigens have been demonstrated to be safe and relatively effective after many long-running trials, the costs of vaccine production remain high due to the required facility for safety precaution. Moreover, no matter how much the technologies of culturing bacteria have been improved, the risk of leaking pathogens causing a disaster remains a threat. Also, the antigens separated by chromatography contain a range of various units of oligosaccharides, which complicates the procedures for quality control. Furthermore, to prepare conjugate vaccines, the partial purified carbohydrate antigens need to be modified to be bound to the immunogenic proteins. In current vaccine production, this modification could occur in the reducing end, nonreducing end, or both terminals of the carbohydrate molecule; therefore, the reactive groups are randomly distributed throughout the sugars, instead of at the most effective location, [6]. On the whole, the conventional vaccines produced from isolated antigens are heterogeneous [7], bear the risk of being contaminated, and likely induce ineffective antibodies, which in turn reduce the titer of effective antibodies induction. Interestingly, these problems can be avoided in 'synthetic vaccines': the specific carbohydrate antigens are obtained by synthesis instead of purifying from pathogens.Using synthetic strategy, we can create vaccines by synthesizing the desired oligosaccharides with definite lengths and equipped linkers bearing the proper reactive group for selective conjugation. Although limited cases showed small epitopes that comprise 3–5 units of monosaccharide residues are sufficient to induce antibody against the whole organism and to confer protection [8], most investigations showed that the capsular polysaccharides of bacteria utilized to prepare vaccines should comprise 10–20 units of monosaccharide residues to turn into effectively immunogenic epitopes [5] (the admissible shortest length of immunogenic sugar is different for various pathogens). The advancements in synthetic methods enable us to obtain long enough polysaccharide molecules with various specific lengths for antibody-binding assay. Through x-ray or NMR analysis, we can have a better understanding of the relationship of the antibody with various lengths of polysaccharide to design more effective vaccines [5]. Over the past several years, despite the fact that some long capsular polysaccharides of bacteria have been synthesized and modified into vaccine candidates, the high costs still prevent synthetic carbohydrate conjugate vaccines from becoming commercially available. To date, there is only one example of an approved fully synthetic carbohydrate conjugate vaccine, one of Haemophilus influenzae serotype b (Hib) vaccine [9].The most challenging step in preparing a synthetic vaccine is to effectively synthesize longer oligosaccharides. The recent leap in the development of oligosaccharide synthesis could make a synthetic vaccine possible in a few years. The 'regioselective one-pot protection' [10], 'programmable one-pot glycosylation' [11], and 'automated solid-phase oligosaccharide synthesis' [12,13] were developed to reduce much synthetic cost by decreasing the synthetic steps and purifying procedures. Unlike the automated solid-phase peptide synthesis that has a well-established standard procedure applied for synthesis of different peptides, the suitable substrates are quite different when different oligosaccharides are synthesized via solid-phase synthesis. Moreover, the excessive reactants necessary to complete each reaction during the solid-phase synthetic processes are wasteful and costly, limiting the application of this strategy in commercial antibacterial vaccine production. The 'solution-phase automated iterative synthesis' [14] was developed to construct oligosaccharides with the traditional chemical synthetic advantage that the reactions are carried out as suitable solution phases, so the activities of substrates are preserved with the solid-synthetic advantage of easy purification.The capsular carbohydrates of bacteria considered as antigens are always polysaccharides with repeating units of oligosaccharides or monosaccharides. For example, the capsular carbohydrate of H. influenzae serotype b (Hib) is a →3-O-D-β-Ribf-(1→1)-D-Ribitol-5→OPO3→ repeating structure. The Neisseria meningitidis type B is encapsulated by α(2→8) polysialic acids, and the N. meningitidis type C is encapsulated by α(2→9) polysialic acids. Such polysaccharides are more likely to be developed into synthetic vaccines, because we can use the minimum number of building blocks and fewer synthetic steps to synthesize the longer oligosaccharides with lower cost. At present, there are two major chemical strategies to synthesize longer oligosaccharides with repeating units. The 'self-condensation strategy', which was used by Verez-Bencomo et al.[9] to synthesize the first licensed synthetic vaccine, always produces a mixture of oligosaccharides with different lengths, and requires careful purification to obtain the effective antigen. On the other hand, 'convergent block synthetic strategy' is an intrinsically better strategy for preparing oligomers or polymers with specific lengths and has been applied to synthesize a number of carbohydrate polymers. However, this strategy is hindered by the limited choices of leaving groups to ensure a proper reactivity and selectivity of an oligosaccharide donor. Typically, when the length of a donor increases, its reactivity and stereo-selectivity decreases. For example, two recent attempts using the 2+2 strategy to construct α(2→9) tetrasialic acids resulted in an inseparable mixture with moderate selectivity (α/β = 1.6:1) [15,16]. Another example also showed that the α-selectivity decreased significantly when the length of sialic acid donor increased from monomer (α only) to tetramer (α/β = 1:1.3) [17]. Encouragingly, a few studies have successfully overcome such a challenge. Mulard and co-workers synthesized the 2-aminoethyl glycosides of a mono-, a deca- and a pentadeca-saccharide made of one, two and three repeating units, respectively, of the Shigella flexneri serotype 2a specific polysaccharide [18]. Recently, we also synthesized the α(2→9) oligosialic acids from dimer to dodecamer via convergent block strategy [19].Beside the chemical synthetic method, the method for the regeneration of expensive sugar nucleotide has been established, and many glycosyltransferases have been discovered and applied successfully to synthesize specific oligosaccharides [20,21]. Compared with chemical strategy, enzymatic synthesis owns several benefits: ▪ The procedures of enzymatic synthesis are simpler without protection and deprotection of polyhydroxy groups;▪ The yields are always high with excellent regioselective and superior stereoselective;▪ The reaction process is green.However, it is very difficult to specify the length of the repeating oligosaccharide with the enzymatic method. The key is to have a template to control the carbohydrate polymerase synthetic efficiency to keep the product in a specific length. Recently, Kiessling [22] and her co-workers have found that galactan polymerization by GlfT2 exhibits a kinetic lag phase, which is eliminated when GlfT2 is reacted with acceptor substrates containing additional Galf residues, suggesting that GlfT2 possesses Galf-binding subsites that contribute to efficient processive chain elongation. This attribute of GlfT2 appears to be a general feature of processive enzymes and can be used to control the repeating oligosaccharide length by carbohydrate polymerase in the near future.The ever progressing development in synthetic methods will eventually allow us to obtain pure oligosaccharides with various specific lengths and well-defined structures, which are critical in structure–activity relationship studies for understanding not only what works better but also how it works in an antibacterial vaccine. The results of these studies will bring us a step closer in creating an ideal synthetic vaccine, which is more effective, more efficient, safer and cheaper for the whole population.Carbohydrate-based vaccines development will be benefitted by advances in carbohydrate synthesis, development in glycan structures analysis methods, and manipulation through the emerging fields of glycochemistry, glycobiology and immunology. Although there have been great advancements on complicated oligosaccharides synthesis by using programmable one-pot or automatic solid-phase methods, no automatic machine is available in the market now. How to design a dream machine for oligosaccharide synthesis will still attract great interest in this field in the coming 5–10 years. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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