Potent inhibitors of the hepatitis C virus NS3 protease:: Design and synthesis of macrocyclic substrate-based β-strand mimics

被引：56

作者：

Goudreau, N ^{[1
]}

Brochu, C ^{[1
]}

Cameron, DR ^{[1
]}

Duceppe, JS ^{[1
]}

Faucher, AM ^{[1
]}

Ferland, JM ^{[1
]}

Grand-Maître, C ^{[1
]}

Poirier, M ^{[1
]}

Simoneau, B ^{[1
]}

Tsantrizos, YS ^{[1
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Dept Chem, Res & Dev, Laval, PQ H7S 2G5, Canada

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2004年 / 69卷 / 19期

关键词：

D O I：

10.1021/jo049288r

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring beta-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.

引用

页码：6185 / 6201

页数：17

共 99 条

[41] Role of charged residues in the catalytic mechanism of hepatitis C virus NS3 protease:: Electrostatic precollision guidance and transition-state stabilization [J].

Koch, U ;

Biasiol, G ;

Brunetti, M ;

Fattori, D ;

Pallaoro, M ;

Steinkühler, C .

BIOCHEMISTRY, 2001, 40 (03) :631-640

[42] Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo [J].

Kolykhalov, AA ;

Mihalik, K ;

Feinstone, SM ;

Rice, CM .

JOURNAL OF VIROLOGY, 2000, 74 (04) :2046-2051

[43] Development of a potent Bcl-xL antagonist based on α-helix mimicry [J].

Kutzki, O ;

Park, HS ;

Ernst, JT ;

Orner, BP ;

Yin, H ;

Hamilton, AD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (40) :11838-11839

[44] Novel P4 truncated tripeptidyl α-ketoamides as HCV protease inhibitors [J].

Lamar, J ;

Victor, F ;

Snyder, N ;

Johnson, RB ;

Wang, QM ;

Glass, JI ;

Chen, SH .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) :263-266

[45] An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus [J].

Lamarre, D ;

Anderson, PC ;

Bailey, M ;

Beaulieu, P ;

Bolger, G ;

Bonneau, P ;

Bös, M ;

Cameron, DR ;

Cartier, M ;

Cordingley, MG ;

Faucher, AM ;

Goudreau, N ;

Kawai, SH ;

Kukolj, G ;

Lagacé, L ;

LaPlante, SR ;

Narjes, H ;

Poupart, MA ;

Rancourt, J ;

Sentjens, RE ;

St George, R ;

Simoneau, B ;

Steinmann, G ;

Thibeault, D ;

Tsantrizos, YS ;

Weldon, SM ;

Yong, CL ;

Llinàs-Brunet, M .

NATURE, 2003, 426 (6963) :186-189

[46] Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain [J].

LaPlante, SR ;

Cameron, DR ;

Aubry, N ;

Lefebvre, S ;

Kukolj, G ;

Maurice, R ;

Thibeault, D ;

Lamarre, D ;

Llinàs-Brunet, M .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (26) :18618-18624

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

LaPlante, SR ;

Aubry, N ;

Bonneau, PR ;

Kukolj, G ;

Lamarre, D ;

Lefebvre, S ;

Li, H ;

Llinàs-Brunet, M ;

Plouffe, C ;

Cameron, DR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (20) :2271-2274

[48] Transferred 13C T1 relaxation at natural isotopic abundance:: A practical method for determining site-specific changes in ligand flexibility upon binding to a macromolecule [J].

LaPlante, SR ;

Aubry, N ;

Déziel, R ;

Ni, F ;

Xu, P .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (50) :12530-12535

[49] Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease:: Towards smaller inhibitors [J].

Llinàs-Brunet, M ;

Bailey, M ;

Fazal, G ;

Ghiro, E ;

Gorys, V ;

Goulet, S ;

Halmos, T ;

Maurice, R ;

Poirier, M ;

Poupart, MA ;

Rancourt, J ;

Thibeault, D ;

Wernic, D ;

Lamarre, D .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (20) :2267-2270

[50] Studies on the C-terminal of hexapeptide inhibitors of the hepatitis C virus serine protease [J].

Llinàs-Brunet, M ;

Bailey, M ;

Déziel, R ;

Fazal, G ;

Gorys, V ;

Goulet, S ;

Halmos, T ;

Maurice, R ;

Poirier, M ;

Poupart, MA ;

Rancourt, J ;

Thibeault, D ;

Wernic, D ;

Lamarre, D .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (19) :2719-2724

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