Acyl sulfonamides as potent protease inhibitors of the hepatitis C virus full-Length NS3 (Protease-Helicase/NTPase): A comparative study of different C-terminals

• Published in: Bioorganic & medicinal chemistry 2003-06, Vol.11 (12), p.2551-2568
• Main Authors: Johansson, Anja, Poliakov, Anton, Åkerblom, Eva, Wiklund, Karin, Lindeberg, Gunnar, Winiwarter, Susanne, Danielson, U.Helena, Samuelsson, Bertil, Hallberg, Anders
• Format: Article
• Language: English
• Subjects: Acylation; Adenosine Triphosphatases - antagonists & inhibitors; Amino Acid Sequence; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; FARMACI; Hepacivirus - drug effects; Hepacivirus - enzymology; Kinetics; Medical sciences; Models, Molecular; NATURAL SCIENCES; NATURVETENSKAP; Oligopeptides - chemistry; Oligopeptides - pharmacology; Pharmacology. Drug treatments; PHARMACY; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; RNA Helicases - antagonists & inhibitors; Serine Endopeptidases - metabolism; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/S0968-0896(03)00179-2

Synthesis and inhibitory potencies of three types of protease inhibitors of the hepatitis C virus (HCV) full-length NS3 (protease-helicase/NTPase) are reported: (i) inhibitors comprising electrophilic serine traps (pentafluoroethyl ketones, α-keto acids, and α-ketotetrazoles), (ii) product-based inhibitors comprising a C-terminal carboxylate group, and (iii) previously unexplored inhibitors comprising C-terminal carboxylic acid bioisosteres (tetrazoles and acyl sulfonamides). Bioisosteric replacement with the tetrazole group provided inhibitors equally potent to the corresponding carboxylates, and substitution with the phenyl acyl sulfonamide group yielded more potent inhibitors. The hexapeptide inhibitors Suc-Asp- d-Glu-Leu-Ile-Cha-Nva-NHSO 2Ph and Suc-Asp- d-Glu-Leu-Ile-Cha-ACPC-NHSO 2Ph with K i values of 13.6 and 3.8 nM, respectively, were approximately 20 times more potent than the corresponding inhibitors with a C-terminal carboxylate and were comparable to the carboxylate-based inhibitor containing the native cysteine, Suc-Asp- d-Glu-Leu-Ile-Cha-Cys-OH ( K i=28 nM). The acyl sulfonamide group constitutes a very promising C-terminal functionality that allows for prime site optimization. Graphic