Exploring Human Parainfluenza Virus Type‑1 Hemagglutinin–Neuraminidase as a Target for Inhibitor Discovery

Human parainfluenza virus type 1 is the major cause of croup in infants and young children. There is currently neither vaccine nor clinically effective treatment for parainfluenza virus infection. Hemagglutinin–neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has be...

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Published inJournal of medicinal chemistry Vol. 57; no. 18; pp. 7613 - 7623
Main Authors El-Deeb, Ibrahim M, Guillon, Patrice, Winger, Moritz, Eveno, Tanguy, Haselhorst, Thomas, Dyason, Jeffrey C, von Itzstein, Mark
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 25.09.2014
Amer Chemical Soc
Subjects
Amides - chemistry
Amides - pharmacology
Animals
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cell Line
Chemistry, Medicinal
Drug Evaluation, Preclinical
HN Protein - chemistry
HN Protein - metabolism
Inhibitory Concentration 50
Life Sciences & Biomedicine
Molecular Dynamics Simulation
Parainfluenza Virus 1, Human - drug effects
Pharmacology & Pharmacy
Protein Conformation
Science & Technology
MOLECULAR-DYNAMICS
ACID
FUSION
ANALOGS
BIOLOGICAL EVALUATION
SIALIDASE
BCX 2798
BIOMOLECULAR SIMULATION
C-4 POSITION
4-GUANIDINO-NEU5AC2EN
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Summary:Human parainfluenza virus type 1 is the major cause of croup in infants and young children. There is currently neither vaccine nor clinically effective treatment for parainfluenza virus infection. Hemagglutinin–neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en)-based inhibitor development. In this study, we explore the effect of C-5 modifications on the potency of Neu5Ac2en derivatives that target the human parainfluenza type-1 hemagglutinin–neuraminidase protein. Our study demonstrates that the replacement of the Neu5Ac2en C-5 acetamido moiety with more hydrophobic alkane-based moieties improves the inhibitory potency for both hemagglutinin–neuraminidase functions. These findings shed light on the importance of C-5 substitution on Neu5Ac2en in the design of novel sialic acid-based inhibitors that target human parainfluenza type-1 hemagglutinin–neuraminidase.
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm500759v