NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain

• Published in: Bioorganic & medicinal chemistry letters 2000-10, Vol.10 (20), p.2271-2274
• Main Authors: LaPlante, Steven R, Aubry, Norman, Bonneau, Pierre R, Kukolj, George, Lamarre, Daniel, Lefebvre, Sylvain, Li, Hong, Llinàs-Brunet, Montse, Plouffe, Céline, Cameron, Dale R
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Hepacivirus - drug effects; Hepacivirus - enzymology; Medical sciences; Molecular Conformation; Nuclear Magnetic Resonance, Biomolecular - methods; Oligopeptides - chemistry; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Protein Conformation; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00466-2

This work describes the use of NMR as a medicinal chemistry tool for better understanding the binding characteristics of inhibitors of the HCV NS3 protease. The protease-bound structure of a tetrapeptide-like inhibitor that has an acid C-terminus, a norvaline at P1 and a naphthylmethoxy proline at P2 is described. Conformational comparisons are made with a similar compound having a 1-amino-cyclopropylcarboxylic acid at P1 and with a hexapeptide inhibitor. Differences between the free and bound states are identified. 19F NMR also helped in determining that a single complex is observed when an inhibitor is added to the protease at a 1:1 ratio.