6C0M

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

Summary for 6C0M

• Entry DOI: 10.2210/pdb6c0m/pdb
• Descriptor: Hemagglutinin-neuraminidase, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: hemagglutinin-neuraminidase, inhibitor, sialic acid, human parainfluenza virus type 3, sialidase, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human respirovirus 3
• Total number of polymer chains: 2
• Total formula weight: 99974.84

Authors

Dirr, L.,Ve, T.,von Itzstein, M. (deposition date: 2018-01-01, release date: 2018-06-27, Last modification date: 2023-10-04)

Primary citation

Pascolutti, M.,Dirr, L.,Guillon, P.,Van Den Bergh, A.,Ve, T.,Thomson, R.J.,von Itzstein, M.
Structural Insights into Human Parainfluenza Virus 3 Hemagglutinin-Neuraminidase Using Unsaturated 3- N-Substituted Sialic Acids as Probes.
ACS Chem. Biol., 13:1544-1550, 2018

PubMed Abstract: 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 IC 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.

PubMed: 29693380
DOI: 10.1021/acschembio.8b00150

Experimental method

X-RAY DIFFRACTION (1.83 Å)