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Synthesis of selective inhibitors against V. cholerae sialidase and human cytosolic sialidase NEU2.

ABSTRACT: Sialidases or neuraminidases catalyze the hydrolysis of terminal sialic acid residues from sialyl oligosaccharides and glycoconjugates. Despite successes in developing potent inhibitors specifically against influenza virus neuraminidases, the progress in designing and synthesizing selective inhibitors against bacterial and human sialidases has been slow. Guided by sialidase substrate specificity studies and sialidase crystal structural analysis, a number of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA or Neu5Ac2en) analogues with modifications at C9 or at both C5 and C9 were synthesized. Inhibition studies of various bacterial sialidases and human cytosolic sialidase NEU2 revealed that Neu5Gc9N(3)2en and Neu5AcN(3)9N(3)2en are selective inhibitors against V. cholerae sialidase and human NEU2, respectively.

SUBMITTER: Khedri Z

PROVIDER: S-EPMC11302589 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Synthesis of selective inhibitors against V. cholerae sialidase and human cytosolic sialidase NEU2.

Khedri Zahra Z Li Yanhong Y Cao Hongzhi H Qu Jingyao J Yu Hai H Muthana Musleh M MM Chen Xi X

Organic & biomolecular chemistry 20120529 30

Sialidases or neuraminidases catalyze the hydrolysis of terminal sialic acid residues from sialyl oligosaccharides and glycoconjugates. Despite successes in developing potent inhibitors specifically against influenza virus neuraminidases, the progress in designing and synthesizing selective inhibitors against bacterial and human sialidases has been slow. Guided by sialidase substrate specificity studies and sialidase crystal structural analysis, a number of 2-deoxy-2,3-dehydro-N-acetylneuraminic ...[more]

PMID: 22641268

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Project description:Neuraminidases (NAs) are critical virulence factors for several microbial pathogens. With a highly conserved catalytic domain, a microbial NA "superfamily" has been proposed. We previously reported that murine polymorphonuclear leukocyte (PMN) sialidase activity was important in leukocyte trafficking to inflamed sites and that antibodies to Clostridium perfringens NA recognized a cell surface molecule(s), presumed to be a sialidase of eukaryotic origin on interleukin-8-stimulated human and murine PMNs. These antibodies also inhibited cell sialidase activity both in vitro and, in the latter instance, in vivo We therefore hypothesized that mammalian sialidases share structural homology and epitopes with microbial NAs. We now report that antibodies to one of the isoforms of C. perfringens NA, as well as anti-influenza virus NA serum, recognize human NEU3 but not NEU1 and that antibodies to C. perfringens NA inhibit NEU3 enzymatic activity. We conclude that the previously described microbial NA superfamily extends to human sialidases. Strategies designed to therapeutically inhibit microbial NA may need to consider potential compromising effects on human sialidases, particularly those expressed in cells of the immune system.IMPORTANCE We previously reported that sialidase activity of human neutrophils plays a critical role in the host inflammatory response. Since the catalytic domains of microbial neuraminidases are highly conserved, we hypothesized that antibodies against Clostridium perfringens neuraminidase might inhibit mammalian sialidase activity. Before the recognition of four mammalian sialidase (Neu) isoforms, we demonstrated that anti-C. perfringens neuraminidase antibodies inhibited human and murine sialidase activity in vivo and in vitro We now show that the antibodies to microbial neuraminidase (C. perfringens and influenza virus) recognize human NEU3, which is important for neural development and cell signaling. Since many microbes that infect mucosal surfaces express neuraminidase, it is possible that the use of sialidase inhibitors (e.g., zanamivir), might also compromise human sialidase activity critical to the human immune response. Alternatively, sialidase inhibitors may prove useful in the treatment of hyperinflammatory conditions.

Project description:Increased sialylation is one of the hallmarks of ovarian cancer (OC) but its relation with programmed cell death is not known. Here we explored the molecular interplay between autophagy, apoptosis/anoikis, and aberrant-expression of the PI3K-Akt/mTOR pathway in the context of sialidase. OC is accompanied by low expression of cytosolic sialidase (Neu2) and ~10-fold more α2,6- than α2,3-linked sialic acids found through qPCR, western blot, and flow cytometry. Interestingly, Neu2 overexpression cleaved α2,6- and α2,3-linked sialic acids and reduced cell viability. Several autophagy-related molecules like LC3B/Atg3/Atg5/Atg7/Atg12/Atg16L1/Beclin1 were upregulated upon Neu2 overexpression. Atg5, a crucial protein for autophagosome formation, was desialylated by overexpressed Neu2. Desialylated Atg5 now showed enhanced association both with Atg12 and Atg16L1 leading to more autophagosome formation. Neu2-overexpressing cells exhibited extrinsic pathway-mediated apoptosis as reflected the in activation of Fas/FasL/FADD/Bid/caspase 8/caspase 6/caspase 3/PARP cleavage. There was also increased Bax, reduced Bcl2, and several cell-cycle molecules (CDK2/CDK4/CDK6/cyclin-B1/cyclin-E). Inhibition of autophagy using bafilomycin A1 or Beclin1 siRNA leads to reversal of Neu2-induced apoptosis suggesting their possible relationship. Additionally, overexpressed Neu2 inhibited growth factor-mediated signaling molecules involved in the PI3K/Akt-mTOR pathway probably through their desialylation. Furthermore, overexpressed Neu2 inhibited epithelial (ZO-1/Claudin1), mesenchymal (snail/slug), and cell-adhesion (integrin-β3/focal-adhesion kinase) molecules suggesting anchorage-dependent cell death (anoikis). Such changes were absent in the presence of bafilomycin A1 indicating the involvement of autophagy in Neu2-induced anoikis. The physiological relevance of our in vitro observations was further confirmed in the OC xenograft model. Taken together, it is the first report demonstrating that Atg5 is a sialoglycoprotein having α2,6- and α2,3-linked sialic acids and its desialylation by overexpressed Neu2 leads to its activation for autophagosome formation, which induced apoptosis/anoikis in OC.

Dataset Information

Synthesis of selective inhibitors against V. cholerae sialidase and human cytosolic sialidase NEU2.

Publications

Synthesis of selective inhibitors against V. cholerae sialidase and human cytosolic sialidase NEU2.

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