6c0m | pdb_00006c0m

The synthesis, biological evaluation and structural insights of unsaturated 3-N-substituted sialic acids as probes of human parainfluenza virus-3 haemagglutinin-neuraminidase

spinqualitylabelsall models 6c0m, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6c0m is a 2 chain structure with sequence from Hpiv-3. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 8LM, BMA, CA, EDO, GOL, MAN, NAG, SO4 Activity: Exo-alpha-sialidase, with EC number 3.2.1.18 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed A novel approach to human parainfluenza virus 3 (hPIV-3) inhibitor design has been evaluated by targeting an unexplored pocket within the active site region of the hemagglutinin-neuraminidase (HN) of the virus that is normally occluded upon ligand engagement. To explore this opportunity, we developed a highly efficient route to introduce nitrogen-based functionalities at the naturally unsubstituted C-3 position on the neuraminidase inhibitor template N-acyl-2,3-dehydro-2-deoxy-neuraminic acid ( N-acyl-Neu2en), via a regioselective 2,3-bromoazidation. Introduction of triazole substituents at C-3 on this template provided compounds with low micromolar inhibition of hPIV-3 HN neuraminidase activity, with the most potent having 48-fold improved potency over the corresponding C-3 unsubstituted analogue. However, the C-3-triazole N-acyl-Neu2en derivatives were significantly less active against the hemagglutinin function of the virus, with high micromolar IC50 values determined, and showed insignificant in vitro antiviral activity. Given the different pH optima of the HN protein's neuraminidase (acidic pH) and hemagglutinin (neutral pH) functions, the influence of pH on inhibitor binding was examined using X-ray crystallography and STD NMR spectroscopy, providing novel insights into the multifunctionality of hPIV-3 HN. While the 3-phenyltriazole- N-isobutyryl-Neu2en derivative could bind HN at pH 4.6, suitable for neuraminidase inhibition, at neutral pH binding of the inhibitor was substantially reduced. Importantly, this study clearly demonstrates for the first time that potent inhibition of HN neuraminidase activity is not necessarily directly correlated with a strong antiviral activity, and suggests that strong inhibition of the hemagglutinin function of hPIV HN is crucial for potent antiviral activity. This highlights the importance of designing hPIV inhibitors that primarily target the receptor-binding function of hPIV HN. Structural Insights into Human Parainfluenza Virus 3 Hemagglutinin-Neuraminidase Using Unsaturated 3- N-Substituted Sialic Acids as Probes.,Pascolutti M, Dirr L, Guillon P, Van Den Bergh A, Ve T, Thomson RJ, von Itzstein M ACS Chem Biol. 2018 Jun 15;13(6):1544-1550. doi: 10.1021/acschembio.8b00150. Epub, 2018 May 21. PMID:29693380 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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