Triazole-linked transition state analogs as selective inhibitors against V. cholerae sialidase

Slack, Teri J.; Li, Wanqing; Shi, Dashuang; McArthur, John B.; Zhao, Guoqun; Li, Yanhong; Xiao, An; Khedri, Zahra; Yu, Hai; Liu, Yang; Chen, Xi

doi:10.1016/j.bmc.2018.10.028

Cited by 15 publications

(20 citation statements)

References 49 publications

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“…Sialidases and neuraminidases are becoming the main targets for drug development as they are playing important roles in bacterial and viral infections. Several derivatives of Neu5Ac2en (DANA) have been designed and synthesized by Chen and co-workers 101 ( Fig. 22 ) as triazole-linked transition state analogs.…”

Section: Neuraminidase Inhibitors (Nais)mentioning

confidence: 99%

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

et al. 2021

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Section: Neuraminidase Inhibitors (Nais)mentioning

confidence: 99%

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

et al. 2021

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“…Percentage Inhibition assays were carried out in duplicates in a 384-well plate similar to that reported previously. 24 All reactions had a final volume of 20 μL containing Neu5Acα2− 3GalβpNP (0.3 mM) and β-galactosidase (12 μg) with 0.1 mM or 1.0 mM of inhibitor. The assay conditions for various sialidases were as follows: A. ureafaciens sialidase (0.5 mU), NaOAc buffer (100 mM, pH 5.5); C. perfringens sialidase (CpNanI, 1.3 mU), 2-(Nmorpholino)ethanesulfonic acid (MES) buffer (100 mM, pH 5.0); V. cholera sialidase (0.6 mU), NaCl (150 mM), CaCl 2 (10 mM), NaOAc buffer (100 mM, pH 5.5); SpNanA (0.75 ng), NaOAc buffer (100 mM, pH 6.0); SpNanB (3 ng), NaOAc buffer (100 mM, pH 6.0); SpNanC (10 ng), MES buffer (100 mM, pH 6.5); PmST1 (0.2 μg), NaOAc buffer (100 mM, pH 5.5), CMP (0.4 mM); hNEU2 (0.6 μg), MES buffer (100 mM, pH 5.0); BiNanH2 (4 ng), NaOAc buffer (100 mM, pH 5.0).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases

Santra

et al. 2019

J. Org. Chem.

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A library of 2(e),3(a/e)-difluorosialic acids and their C-5 and/or C-9 derivatives were chemoenzymatically synthesized. Pasteurella multocida sialic acid aldolase (PmAldolase), but not its Escherichia coli homolog (EcAldolase), was found to catalyze the formation of C5-azido analog of 3-fluoro(equatorial)-sialic acid. In comparison, both PmAldolase and EcAldolase could catalyze the synthesis of 3-fluoro (axial or equatorial)-sialic acids and their C-9 analogs although PmAldolase was generally more efficient. The chemoenzymatically synthesized 3-fluoro (axial or equatorial)-sialic acid analogs were purified and chemically derivatized to form desired difluorosialic acids and derivatives. Inhibition studies against several bacterial sialidases and a recombinant human cytosolic sialidase hNEU2 indicated that sialidase inhibition was affected by the C-3 fluorine stereochemistry and derivatization at C-5 and/or C-9 of the inhibitor. Opposite to that observed for influenza A virus sialidases and hNEU2, compounds with an axial fluorine at C-3 were better inhibitors (up to 100-fold) against bacterial sialidases compared to their 3Fequatorial counterparts. While C-5-modified compounds were less efficient anti-bacterial sialidase inhibitors, 9-N 3 -modified 2,3-difluoro-Neu5Ac showed increased inhibitory activity against bacterial sialidases. 9-Azido-9-deoxy-2-equatorial-3-axial-difluoro-N-acetylneuraminic acid (2e3aDFNeu5Ac9N 3 ) was identified as an effective inhibitor with a long effective duration selectively against pathogenic bacterial sialidases from Clostridium perfringens (CpNanI) and V. cholerae.

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“…These compounds displayed weak inhibition, but were improved in more recent work combining the aforementioned C2, C3-difluoro additions to produce a covalent inhibitor (11) ( Li et al, 2019 ). Conjugation of a small peptide (1-4 residues) to the C9 position of Neu5Ac2en via a triazole linkage has been attempted and showed high selectivity for V. cholerae SA, with low micromolar IC 50 values (12) ( Slack et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

Bowles

Gloster

2021

Front. Mol. Biosci.

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Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.

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Triazole-linked transition state analogs as selective inhibitors against V. cholerae sialidase

Cited by 15 publications

References 49 publications

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases

Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

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