Hepatitis C virus (HCV) NS3 protease inhibitor | BI-1388
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Highlights
BI-1388 binds to the active site of NS3 that is located in the shallow and broad protein-protein interaction surface of the protease- and the helicase domain of the enzyme. It is a nanomolar to picomolar inhibitor of protease activity and of viral replication for various HCV genotypes and for resistant mutants D168V and R155K. BI-1388 was shown to be highly selective against other serine/cysteine proteases, and it is characterised by an exceptional liver partitioning.
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Target information
HCV NS3 protease is a 180-amino acid chymotrypsin-like serine protease. Its function is the auto-proteolytic cleavage of HCV viral polyprotein (~3000 aa) into individual, non-structural (NS) proteins with various functions. Thus it is an essential component of HCV replication and infectivity. The NS3 protein contains two functional domains: a serine protease- and a helicase domain. The active site of NS3 is located in the shallow and wide protein-protein interaction surface of these domains. BI-1388 and other known NS3 inhibitors cover significant parts of this interaction surface in addition to the active site. Boehringer Ingelheim was the first company to establish proof-of-concept in humans for an HCV NS3 protease inhibitor as a treatment of HCV infection.4
BI-1388 bound to the active site of NS3 (PDB code: 4i31)3
In vitro Activity
|
Probe name |
BI-1388 |
|
MW [Da] |
820 |
|
IC50 [nM]a, WT enzyme, genotype 1a |
0.48 |
|
IC50 [nM]a, WT enzyme, genotype 1b |
1.1 |
|
IC50 [nM]a, WT enzyme, genotype 2a |
0.14 |
|
IC50 [nM]a, WT enzyme, genotype 3a |
12 |
|
IC50 [nM]a, WT enzyme, genotype 4a |
0.23 |
|
IC50 [nM]a, WT enzyme, genotype 5a |
0.24 |
|
IC50 [nM]a, WT enzyme, genotype 6a |
0.16 |
|
IC50 [nM]a, R155K, genotype 1a |
4.7 |
|
IC50 [nM]a, D168V, genotype 1a |
58 |
|
IC50 [nM]a, A156T, genotype 1b |
2.7 |
|
IC50 [nM]a, D156V, genotype 1b |
4.3 |
|
IC50 [nM]a, D168A, genotype 1b |
16 |
|
IC50 [nM]a, D168V, genotype 1b |
15 |
|
EC50 [nM], WT, replicon assay, genotype 1ab |
0.11 |
|
EC50 [nM], R155K, replicon assay, genotype 1ab |
1.0 |
|
EC50 [nM], WT, replicon assay, genotype 1bb |
0.11 |
|
EC50 [nM], D168V, replicon assay, genotype 1bb |
0.14 |
a Enzymatic assay, see ref. 3 for assay details
b Cell-based HCV RNA replication Luciferase reporter assay, see ref. 3 for assay details
In vitro DMPK parameters
|
Probe name |
BI-1388 |
|
Solubility @ pH 7 [µg/ml] |
3.4 |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
10 |
|
CACO efflux ratio |
1.2 |
|
Microsomal stability: t½ [min], RLM |
138 |
|
Plasma protein binding human [%QH] |
99.800 |
In vivo DMPK parameters
Pharmacokinetic profile of BI-1388 in rat a
|
Route |
BI-1388 |
BI-1388 |
|
i.v. |
CL [ml/min/kg] |
19 |
|
T ½ (h) |
2.6 |
|
|
Vss [l/kg]b |
0.97 |
|
|
|
F(%) |
14 |
|
p.o. |
Cmax(µM) |
1.3 |
|
AUC0-inf(µM*h) |
1.4 |
a Dose = i.v., 4 mg/kg (70% PEG-400 and 30% water); p.o., 10 mg/kg (1% MP, 0.3% Tween-80, and Methocel 0.5%)
Selectivity
Co-crystal structure of the BI probe compound and the target protein
An X-ray structure of BI-1388 in complex with NS3 is available (PDB code: 4i31, 4i32, 4i33 – complexes with WT and resistant mutants D168V and R155K)
reference molecules
For a recent review of HCV NS3 protease inhibitors see reference 6.
Summary
BI-1388 is a nanomolar to picomolar inhibitor of HCV NS3 protease activity and of viral replication for various HCV genotypes and for resistant mutants D168V and R155K.
Supplementary data
References
Macrocyclic Inhibitors of the NS3 Protease as Potential Therapeutic Agents of Hepatitis C Virus Infection
Y. S. Tsantrizos, G. Bolger, P. Bonneau, D. R. Cameron, N. Goudreau, G. Kukolj, S. R. LaPlante, M. Llinàs-Brunet, H. Nar, D. Lamarre
Angw. Chem. Int. Ed. 2003, 42, 1355-1360.
A Highly Convergent and Efficient Synthesis of a Macrocyclic Hepatitis C Virus Protease Inhibitor BI 201302
X. Wei, C. Shu, N. Haddad, X. Zeng, N. D. Patel, Z. Tan, J. Liu, H. Lee, S. Shen, S. Campbell, R. J. Varsolona, C. A. Busacca, A. Hossain, N. K. Yee, C. H. Senanayake
Org. Lett. 2013, 15, 1016-1019.
Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance
J. A. O'Meara, C. T. Lemke, C. Godbout, G. Kukolj, L. Lagacé, B. Moreau, D. Thibeault, P. W. White, M. Llinàs-Brunet
J. Biol. Chem. 2013, 288, 5673-5681.
An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
D. Lamarre, P. C. Anderson, M. Bailey, P. Beaulieu, G. Bolger, P. Bonneau, M. Bös, D. R. Cameron, M. Cartier, M. G. Cordingley, A. M. Faucher, N. Goudreau, S. H. Kawai, G. Kukolj, L. Lagacé, S. R. LaPlante, H. Narjes, M. A. Poupart, J. Rancourt, R. E. Sentjens, R. St George, B. Simoneau, G. Steinmann, D. Thibeault, Y. S. Tsantrizos, S. M. Weldon, C. L. Yong, M. Llinàs-Brunet
Nature 2003, 426, 186-189.
Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution
B. Moreau, J. A. O’Meara, J. Bordeleau, M. Garneau, C. Godbout, V. Gorys, M. Leblanc, E. Villemure, P. W. White, M. Llinàs-Brunet
J. Med. Chem. 2014, 57, 1770-1776.
Hepatitis C virus NS3/4a protease inhibitors
J. A. McCauley, T. M. Rudd
Curr. Opin. Pharmacol. 2016, 30, 84-92.
