Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors

[Display omitted] The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemica...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-03, Vol.28 (5), p.906-909
Main Authors: Namoto, Kenji, Sirockin, Finton, Sellner, Holger, Wiesmann, Christian, Villard, Frederic, Moreau, Robert J., Valeur, Eric, Paulding, Stephanie C., Schleeger, Simone, Schipp, Kathrin, Loup, Joachim, Andrews, Lori, Swale, Ryann, Robinson, Michael, Farady, Christopher J.
Format: Article
Language:English
Subjects:
3C Viral Proteases
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Covalent inhibitor
Crystallography, X-Ray
Cysteine Endopeptidases - metabolism
Cysteine Proteinase Inhibitors - chemical synthesis
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - pharmacology
Dose-Response Relationship, Drug
Drug Design
Humans
Macrocycle
Macrocyclic Compounds - chemical synthesis
Macrocyclic Compounds - chemistry
Macrocyclic Compounds - pharmacology
Microbial Sensitivity Tests
Models, Molecular
Molecular Conformation
Protease inhibition
Rhinovirus - drug effects
Rhinovirus - enzymology
Rhinovirus 3C protease
Solid phase synthesis
Structure-Activity Relationship
Structure-based drug design
Viral Proteins - antagonists & inhibitors
Viral Proteins - metabolism
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Description
Summary:[Display omitted] The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.01.064