Sialidase-involved One-pot Multienzyme (OPME) Synthesis of Sialidase Inhibitors and Sialosides

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  • Sialidase-involved One-pot Multienzyme (OPME) Synthesis of Sialidase Inhibitors and Sialosides Book Detail

  • Author : An Xiao
  • Release Date : 2018
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  • ISBN 13 : 9780438629356
  • File Size : 62,62 MB
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Sialidase-involved One-pot Multienzyme (OPME) Synthesis of Sialidase Inhibitors and Sialosides by An Xiao PDF Summary

Book Description: Streptococcus pneumoniae strains have up to three sialidases, including SpNanA, SpNanB, and/or SpNanC. SpNanA is a hydrolytic sialidase generating free sialic acids from sialic acid-containing compounds. SpNanB is an intramolecular (IT) trans-sialidase which produces 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac). SpNanC is a unique sialidase which produces a sialidase transition state analog inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (Neu5Ac2en, DANA). The Streptococcus pneumoniae sialidases SpNanA and SpNanB are important virulence factors that are essential for streptococcal infection of upper and lower respiratory tract. Generally, microbial sialidases are closely related to the invasion, colonization and nutrition of pathogens including both viruses and bacteria, and thus attractive targets for designing inhibitors as potent antimicrobial therapeutics. The synthesis of sialidase inhibitors such as Neu5Ac2en and its derivatives has been actively pursued due to their therapeutic efficacy. During my doctoral research, I aimed at developing new one-pot multienzyme (OPME) methods for the synthesis of sialidase inhibitors and sialosides, taking advantage of the activities of Streptococcus pneumoniae sialidases SpNanC and SpNanB. Sialidase transition state analog inhibitor Neu5Ac2en has played a leading role in developing clinically used anti-influenza virus drugs. Based on the unique Neu5Ac2en-forming catalytic property of Streptococcus pneumoniae sialidase SpNanC, an effective one-pot multienzyme (OPME) strategy was developed to directly access Neu5Ac2en and its C-5, C-9, and C-7-analogs from N-acetylmannosamine (ManNAc) and derivatives. The obtained Neu5Ac2en analogs were further derivatized at various positions to generate a larger library of sialidase inhibitors. Inhibition studies demonstrated improved selectivity of several C-5- or C-9-modified Neu5Ac2en derivatives against several bacterial sialidases. The study provides an efficient enzymatic method to access sialidase inhibitors with improved selectivity. This study is described in Chapter 2. 2,7-Anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac) is the product of SpNanB. It can be a potential prebiotic capable of serving as the sole carbon source of a common human gut commensal anaerobic bacterium Ruminococcus gnavus. Chapter 3 describes a one-pot multienzyme (OPME) system for synthesizing 2,7-anhydro-Neu5Ac and its derivatives. Based on crystal structure analysis, an N-cyclohexyl derivative of 2,7-anhydro-neuraminic acid is designed, synthesized, and shown to be a selective inhibitor against SpNanB and another Streptococcus pneumoniae sialidase SpNanC. This study demonstrates a new strategy of synthesizing 2,7-anhydro-sialic acids in gram scale and the potential application of their derivatives as selective sialidase inhibitors. Sia2ens are common byproducts of chemical sialylation reactions. Chapter 4 describes the development of several chemical and chemoenzymatic methods for utilizing Sia2ens as starting materials to synthesize sialosides. Neu5Ac2en was used directly as the sialyl donor for SpNanC-catalyzed synthesis of a simple [alpha]-linked sialoside Neu5Ac[alpha]OMe in the presence of methanol. A one-pot multienzyme (OPME) method was also developed using Sia2ens as the synthon for enzymatic synthesis of sialosides. For Sia2ens that cannot be hydrated by SpNanC, chemical methods were developed to convert the Sia2ens to the corresponding sialic acids. The latter was used to synthesize a selective number of sialic acids and sialosides including those containing 4-acetamido-4-deoxy Neu5Ac (Neu5Ac4NAc), a stable analog of 4-O-acetyl Neu5Ac (Neu4,5Ac2). The Neu5Ac4NAc obtained will be used for future cell feeding studies and for synthesizing sialosides for binding studies.

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