Involvement of complex glycostructures in a variety of damaging and healing processes has already been acknowledged by development of carbohydrate-based vaccines and therapeutics. The bacteria Streptococcus pneumoniae (SPn) have become one of the most frequent causes of pneumonia, bacteremia, and meningitis in the elderly, immunocompromised, and especially in young children. SPn has one of the largest public health and economic impacts amongst all bacterial infectious diseases. Over 2 million children die annually worldwide due to pneumonia, accounting for almost 20% of deaths under age five with more than half of these deaths attributed to SPn. Amongst over ninety elucidated SPn serotypes, 6A and 6B are nearly equally important causes of bacterial infections. Serotypes SPn6A and 6B account for 4.7 and 7%, respectively, of all cases of invasive pneumococcal disease in the US and the SPn6-serogroup has been consistently ranked within the top three causes of invasive pneumococcal disease worldwide. Since the SPn bacterial cell is surrounded by a polysaccharide capsule, preventive vaccination is a viable tool against the bacterial invasion. Usually, serotype-specific antibodies are formed in response;even so it was believed that due to similarity in the carbohydrate core structures of SPn6A and 6B, the elicited antibodies would be cross-reactive. As a result, only hydrolytically stable SPn6B was included in all currently licensed multi-component vaccines. Recent studies challenged hypothesis of the cross-reactivity and the importance of including the SPn6A conjugates in the future generations of anti-SPn vaccines has been acknowledged. However, the achievement of this is challenging for a number of reasons, major of which is low availability of pure isolates. Herein, development of an expeditious strategy to obtain synthetic equivalents of saccharides of SPn6-serogroup and conjugates thereof to ensure reliable and reproducible immunological studies is proposed. Additional interest to the serogroup SPn6 has recently been drawn by a discovery of a new serotype 6C that differs by two structural units from 6B. It has been postulated that the significant structural difference from the currently used serotype SPn6B may lead to a weak cross-protection against 6C and could result in an outbreak of 6C-derived pneumococcal infections, just as it previously occurred for serotype SPn19A. The first total synthesis of oligosaccharides of the newly arisen serotype and conjugates thereof for collaborative immunological studies is proposed herein. The long-term goal of the PI's research is to make synthetic complex carbohydrates and glycoconjugates more accessible to general chemical, biochemical, and industrial audiences to keep pace with the exploding area of glycobiology. The ultimate goal of the proposed project is to develop a fully synthetic vaccine component, specific to the serotypes SPn6A and 6C (or universal for serogroup 6), suitable for implementing in the future generations of multi-serotype anti-SPn vaccines. Supported by promising preliminary results, the application of a new thioimidate glycosylation method in the synthesis of glycostructures to study immunological properties of SPn6A is proposed. The synthetic saccharides will be then converted into polyvalent glycoconjugates whose immunological properties will be determined in collaboration with Professor Moon Nahm at the University of Alabama at Birmingham. The objective of this application is to develop a general approach to the synthesis of novel glycoconjugates structurally related to SPn6-serogroup, an important cause of bacterial infections.
The health benefits of the proposed research include the potential to discover new and effective glycotherapeutics to fight bacterial infections in humans. Other benefits to the biomedical community include the discovery of new effective synthetic strategies to sequence complex carbohydrates and glycoconjugates, thereby creating new chemical ways to approach major challenges of modern medical sciences. An important aspect of this research is the training that young researchers working on these projects will receive. During their laboratory experience they do not only learn important tools that allow chemists to synthesize, modify and analyze organic molecules, but also develop new synthetic methodologies and participate in the elaboration of state of the art multi-step syntheses. The researchers are exposed to strategy development and collaborative biological experimentations to solve various biomedical puzzles, therefore, building an essential bridge between chemistry, biology, and medicine.
| Hasty, Scott J; Kleine, Matthew A; Demchenko, Alexei V (2011) S-Benzimidazolyl glycosides as a platform for oligosaccharide synthesis by an active-latent strategy. Angew Chem Int Ed Engl 50:4197-201 |
| Kaeothip, Sophon; Demchenko, Alexei V (2011) On orthogonal and selective activation of glycosyl thioimidates and thioglycosides: application to oligosaccharide assembly. J Org Chem 76:7388-98 |
| Parameswar, Archana R; Park, In Ho; Saksena, Rina et al. (2009) Synthesis, conjugation, and immunological evaluation of the serogroup 6 pneumococcal oligosaccharides. Chembiochem 10:2893-9 |
