Boehringer Ingelheim (canada) Ltd.

Boehringer Ingelheim International Gmbh

Boehringer Ingelheim Gmbh

Boehringer Ingelheim Pharma Gmbh & Co Kg

George Kukolj

Pierre Louis Beaulieu

James Gillard

Gulrez Fazal

Eric Jolicoeur

Volkhard Austel

Jean Rancourt

Youla S Tsantrizos

Martin Poirier

Sylvie Goulet

Arnim Pause

Marc-Andre Poupart

Marc-André Poupart

Daniel Lamarre

Steven LaPlante

René Coulombe

Ginette McKercher

Lisette Lagacé

Martin Marquis

Lisette Lagace

Ginette Mckercher

A unique HCV RNA molecule is provided having an enhanced efficiency of establishing cell culture replication. Novel adaptive mutations have been identified within the HCV non-structural region that improves the efficiency of establishing persistently replicating HCV RNA in cell culture. This self-replicating polynucleotide molecule contains, contrary to all previous reports, a 5'-NTR that can be either an A as an alternative to the G already disclosed and therefore provides an alternative to existing systems comprising a self-replicating HCV RNA molecule. The G&#x2192;A mutation gives rise to HCV RNA molecules that, in conjunction with mutations in the HCV non-structural region, such as the G(2042)C/R mutations, possess greater efficiency of transduction and/or replication. These RNA molecules when transfected in a cell line are useful for evaluating potential inhibitors of HCV replication.

Self-replicating RNA molecule from hepatitis C virus

An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein: wherein Rand Rand Q are as defined herein;

Viral polymerase inhibitors

An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein:

A compound of the formula I: wherein: X is CH or N; Y is O or S; Z is OH, NH, NMeR, NHR; ORor 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents; A is N, CORor CR, wherein Ris H, halogen, or (C) alkyl and Ris H or (Calkyl), with the proviso that X and A are not both N; Ris H, halogen, (Calkyl) or OR, wherein Ris H or (Calkyl); The compounds of the invention may be used as inhibitors of hepatitis C virus replication. The invention further provides a method for treating or preventing hepatitis C virus infection.

The HCV NS5B polymerase, when complexed with certain inhibitors, adopts a conformation in which the finger loop region defined by amino acid residues 18 to 35 is displaced to expose a binding pocket defined generally by amino acid residues 392, 393, 395, 396, 399, 424, 425, 428, 429, 492, 493, 494, 495, 496, 500 and 503. This newly exposed binding pocket defines a novel target in the search of further chemical entities which are capable of binding to HCV NS5B and modulating, or preferably inhibiting, the polymerase activity of HCV NS5B.

Hepatitis C Virus NS5B polymerase inhibitor binding pocket

A unique HCV RNA molecule is provided having an enhanced efficiency of establishing cell culture replication. Novel adaptive mutations have been identified within the HCV non-structural region that improves the efficiency of establishing persistently replicating HCV RNA in cell culture. This self-replicating polynucleotide molecule contains, contrary to all previous reports, a 5'-NTR that can be either an A as an alternative to the G already disclosed and therefore provides an alternative to existing systems comprising a self-replicating HCV RNA molecule. The G--&#x3e;A mutation gives rise to HCV RNA molecules that, in conjunction with mutations in the HCV non-structural region, such as the G(2042)C/R mutations, possess greater efficiency of transduction and/or replication. These RNA molecules when transfected in a cell line are useful for evaluating potential inhibitors of HCV replication.

A method for identifying compounds binding to HCV polymerase comprising the steps of: contacting said HCV polymerase or an analog thereof with a probe formula I: wherein A is O, S, N, NR, or CR, wherein Ris defined herein; wherein Rand Rand Q are as defined herein;

Direct binding assay for identifying inhibitors of HCV polymerase

An inhibitor-resistant HCV NS3 protease is provided which is useful to screen for compounds having therapeutic value against drug resistant HCV strains. In particular, the inhibitor-resistant HCV NS3 protease comprises an amino acid sequence which is mutated in the substrate binding pocket thereof rendering the protease resistant to inhibitor. In a specific aspect of the present invention, at least one of the amino acids at position 155, 156 and 168 of the HCV NS3 protease is mutated to yield an inhibitor-resistant protease.

Inhibitor-resistant HCV NS3 protease

A unique HCV RNA molecule is provided having an enhanced efficiency of establishing cell culture replication. Novel adaptive mutations have been identified within the HCV non-structural region that improves the efficiency of establishing persistently replicating HCV RNA in cell culture. This self-replicating polynucleotide molecule contains, contrary to all previous reports, a 5'-NTR that can be either an A as an alternative to the G already disclosed and therefore provides an alternative to existing systems comprising a self-replicating HCV RNA molecule. The G-&#x3e;A mutation gives rise to HCV RNA molecules that, in conjunction with mutations in the HCV non-structural region, such as the G(2042)C/R mutations, possess greater efficiency of transduction and/or replication. These RNA molecules when transfected in a cell line are useful for evaluating potential inhibitors of HCV replication.

An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I:wherein Ris selected from: H, haloalkyl, (C)alkyl, (C)alkenyl, (C)cycloalkyl, (C)alkynyl, (C)cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted;

Growing community of inventors

Laval, Canada

George Kukolj