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Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds.

ABSTRACT: The relative reactivities of C-4 and C-7 azides derived from zanamivir were compared in cycloaddition reactions with a panel of alkynes. All of the reactions proceeded efficiently with no observable differences between primary and secondary azides. Significant rate differences were observed between several members of the alkyne panel. Most notably, a trialkyne derived from a 1,3,5-triazine core underwent complete reaction within 4 h, whereas an analogous trialkyne with an all carbon aromatic core required 18 h. These results suggest that the triazine core serves as an internal catalyst.

SUBMITTER: Lu Y

PROVIDER: S-EPMC2190540 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds.

Lu Yan Y Gervay-Hague Jacquelyn J

Carbohydrate research 20070609 12-13

The relative reactivities of C-4 and C-7 azides derived from zanamivir were compared in cycloaddition reactions with a panel of alkynes. All of the reactions proceeded efficiently with no observable differences between primary and secondary azides. Significant rate differences were observed between several members of the alkyne panel. Most notably, a trialkyne derived from a 1,3,5-triazine core underwent complete reaction within 4 h, whereas an analogous trialkyne with an all carbon aromatic cor ...[more]

PMID: 17597592

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Project description:Influenza A virus (IAV) binds its host cell using the major viral surface protein hemagglutinin (HA). HA recognizes sialic acid, a plasma membrane glycan that functions as the specific primary attachment factor (AF). Since sialic acid alone cannot fulfill a signaling function, the virus needs to activate downstream factors to trigger endocytic uptake. Recently, the epidermal growth factor receptor (EGFR), a member of the receptor-tyrosine kinase family, was shown to be activated by IAV and transmit cell entry signals. However, how IAV's binding to sialic acid leads to engagement and activation of EGFR remains largely unclear. We used multicolor super-resolution microscopy to study the lateral organization of both IAV's AFs and its functional receptor EGFR at the scale of the IAV particle. Intriguingly, quantitative cluster analysis revealed that AFs and EGFR are organized in partially overlapping submicrometer clusters in the plasma membrane of A549 cells. Within AF domains, the local AF concentration reaches on average 10-fold the background concentration and tends to increase towards the cluster center, thereby representing a multivalent virus-binding platform. Using our experimentally measured cluster characteristics, we simulated virus diffusion on a flat membrane. The results predict that the local AF concentration strongly influences the distinct mobility pattern of IAVs, in a manner consistent with live-cell single-virus tracking data. In contrast to AFs, EGFR resides in smaller clusters. Virus binding activates EGFR, but interestingly, this process occurs without a major lateral EGFR redistribution, indicating the activation of pre-formed clusters, which we show are long-lived. Taken together, our results provide a quantitative understanding of the initial steps of influenza virus infection. Co-clustering of AF and EGFR permit a cooperative effect of binding and signaling at specific platforms, thus linking their spatial organization to their functional role during virus-cell binding and receptor activation.

Dataset Information

Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds.

Publications

Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds.

Similar Datasets

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