5W2U

INFLUENZA VIRUS NEURAMINIDASE N9 IN COMPLEX WITH 7-DEOXYGENATED 2,3-DIFLUORO-N-ACETYLNEURAMINIC ACID

Summary for 5W2U

• Entry DOI: 10.2210/pdb5w2u/pdb
• Related: 5W26 5W2W 5W2Y
• Descriptor: Neuraminidase, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: influenza virus neuraminidase, n9, complex, 7-deoxy 2, 3-difluorosialic acid, second binding site, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus (strain A/Tern/Australia/G70C/1975 H11N9)
• Cellular location: Virion membrane : P03472
• Total number of polymer chains: 1
• Total formula weight: 46709.47

Authors

Streltsov, V.A.,Mckimm-Breschkin, J.,Barrett, S.,Pilling, P.,Hader, S.,Watt, A.G. (deposition date: 2017-06-06, release date: 2018-02-21, Last modification date: 2024-10-16)

Primary citation

McKimm-Breschkin, J.L.,Barrett, S.,Pilling, P.A.,Hader, S.,Watts, A.G.,Streltsov, V.A.
Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro- N-acetylneuraminic Acid Derivatives.
J. Med. Chem., 61:1921-1933, 2018

PubMed Abstract: Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5- N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro-β-l-manno-2-nonulopyranosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency.

PubMed: 29397718
DOI: 10.1021/acs.jmedchem.7b01467

Experimental method

X-RAY DIFFRACTION (2 Å)