Structural and functional-group tuning in the design of neuraminidase inhibitors

• Published in: Carbohydrate research Vol. 267; no. 2; pp. 239 - 261
• Main Authors: Sabesan, Subramaniam, Neira, Susana, Wasserman, Zelda
• Format: Journal Article
• Language: English
• Published: AMSTERDAM Elsevier Ltd 17.02.1995; Elsevier
• Subjects: Amino Sugars - chemistry; Amino Sugars - pharmacology; Biochemistry & Molecular Biology; Carbohydrate Conformation; Carbohydrate Sequence; Chemistry; Chemistry, Applied; Chemistry, Organic; Disaccharides - chemistry; Disaccharides - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Galactose - chemistry; Galactose - metabolism; Glycosides - biosynthesis; Glycosides - chemistry; Influenza virus neuraminidase; Kinetics; Life Sciences & Biomedicine; Molecular Sequence Data; Molecular Structure; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Neuraminidase inhibitors; Orthomyxoviridae - enzymology; Physical Sciences; Protein Binding; Science & Technology; Sialic Acids - chemistry; Sialic Acids - metabolism; Structure-Activity Relationship; Substrate Specificity; Neuraminidase inhibitors; Structure-activity relationship; Influenza virus neuraminidase; ANALOGS; STRUCTURE-ACTIVITY RELATIONSHIP; NUCLEAR-MAGNETIC-RESONANCE; RECEPTOR; SIALIC-ACID; C-4; A VIRUS; NEURAMINIDASE INHIBITORS; INFLUENZA VIRUS NEURAMINIDASE; CLUSTER SIALOSIDE INHIBITORS; BINDING; N-ACETYLNEURAMINIC ACID; INFLUENZA-VIRUS HEMAGGLUTININ
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/0008-6215(94)00309-4

Analogues of the disaccharide α- NeuAc-(2 → 6)-β- d- Gal-OR have been made by modifications at C-1 and C-6 of the galactose and at C-4 of the NeuAc unit, for structure-activity relationship studies with influenza virus neuraminidase. These studies indicate that for the influenza neuraminidase, a larger aglycon at C-1 of galactose is less preferred, whereas the restriction of the rotamer orientation at C-6 of galactose in the “tg” mode favors enzyme binding. Substitution at C-4 of the NeuAc unit has the most profound effect in the influenza neuraminidase hydrolysis and inhibition. For example, azido and acetamido groups at C-4 of the NeuAc units render the sialosides resistant to neuraminidase hydrolysis. However, these derivatives are not inhibitors of the neuraminidase, indicating their lack of binding. On the other hand, a 4-amino substitution of the NeuAc unit not only renders the corresponding sialosides neuraminidase-resistant, but also makes them potent neuraminidase inhibitors. This potent inhibition indicates that the 4-amino groups in these sialosides may engage in favorable interaction with amino acids at the neuraminidase active-site. The conclusion is also supported by docking studies of the carbohydrate structures at the neuraminidase active-site.