2'-BRANCHED NUCLEOSIDES AND FLAVIVIRIDAE MUTATION

• US 20110129813A1
• Filed: 10/28/2010
• Published: 06/02/2011
• Est. Priority Date: 11/15/2002
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: David N. Standring, Jean-Pierre Sommadossi, Lin Qu, Paolo Lacolla, Vadim Bichko
• Inventors: Sommadossi, Jean-Pierre, Qu, Lin, LaColla, Paolo, Bichko, Vadim, Standring, David N.
• Granted Patent: US 8,674,085 B2
• Time in Patent Office: Days
• US Class Current: 435/5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2770/24022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2770/24122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2770/24222 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12Q 1/04 Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor C12Q1/6897 takes precedence
• CPC Class Codes: C12Q 1/18 : Testing for antimicrobial activity of a material
• CPC Class Codes: C12Q 1/701 : Specific hybridization probes
• CPC Class Codes: C12Q 1/707 : non-A, non-B Hepatitis, excluding hepatitis D
• CPC Class Codes: C12Q 2600/156 : Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 : Expression markers
• CPC Class Codes: G01N 2333/186 : Hepatitis C; Hepatitis NANB
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention discloses a method for the treatment of Flaviviridae infection that includes the administration of a 2′-branched nucleoside, or a pharmaceutically acceptable prodrug and/or salt thereof, to a human in need of therapy in combination or alternation with a drug that directly or indirectly induces a mutation in the viral genome at a location other than a mutation of a nucleotide that results in a change from serine to a different amino acid in the highly conserved consensus sequence, XRXSGXXXT, of domain B of the RNA polymerase region, or is associated with such a mutation; The invention also includes a method to detect a mutant strain of Flaviviridae and a method for its treatment.

Claims

1-86. -86. (canceled)

87. A method for identifying viral resistance in a host infected with a hepatitis C virus comprising detecting the presence of an amino acid 282 Ser to Thr mutation in the RNA polymerase region of the hepatitis C virus.

89. The method of claim 87, wherein the viral resistance is to a 2′

-branched nucleoside.

90. The method of claim 87, wherein the viral resistance is to a 2′

-C-methyl-branched nucleoside.

91. The method of claim 87, wherein identifying viral resistance comprises assaying the blood of the host to test for seroconversion from wild-type to mutant hepatitis C virus.

92. The method of claim 87, wherein identifying viral resistance comprises phenotypic analysis of viral plaque growth from a viral culture sample from the host.

93. The method of claim 92, wherein the phenotypic analysis comprises

(i) obtaining a viral culture sample from the host;

(ii) culturing the sample and comparing the plaque growth between the sample and wild type virus; and

(iii) determining whether the plaque growth of the sample is smaller than the plaque growth of the wild-type virus.

94. The method of claim 87, wherein identifying viral resistance comprises determination of the replication fitness of the virus.

95. The method of claim 94, wherein determination of the replication fitness of the virus comprises

(i) obtaining a viral culture sample from the host;

(ii) determining the replication fitness of the sample virus; and

(iii) determining whether the replication fitness of the sample virus is less than the replication fitness of the wild-type virus.

96. The method of claim 87, wherein identifying viral resistance comprises

(i) contacting a sample containing a hepatitis C virus nucleic acid sequence with a detectable oligonucleotide probe having a sequence complementary to a codon that encodes a serine in the highly conserved consensus sequence, XRXSGXXXT, of domain B of the RNA polymerase region of the hepatitis C virus;

(ii) allowing the probe to hybridize to the sequence; and

(iii) detecting the hybridization of the probe the sequence.

97. The method of claim 96, wherein the oligonucleotide probe of step (i) is designed to identify cytidine at nucleotide 8443 of the RNA polymerase region of the hepatitis C virus.

88. A method for identifying viral resistance in a host infected with a hepatitis C virus comprising detecting the presence of a G to C mutation of nucleotide 8443 of the hepatitis C virus genome.

98. An array for the identification of a drug resistant hepatitis C virus comprising an oligonucleotide probe having a sequence complementary to a codon that encodes a serine in the highly conserved consensus sequence, XRXSGXXXT, of domain B of the RNA polymerase region of the hepatitis C virus.

99. The array of claim 98, wherein the oligonucleotide probe is designed to identify cytidine at nucleotide 8443 of the RNA polymerase region of the hepatitis C virus.

100. A kit for the identification of viral resistance in a host infected with a hepatitis C virus comprising:

(i) an oligonucleotide complementary to a codon that encodes a serine in the highly conserved consensus sequence, XRXSGXXXT, of domain B of the RNA polymerase region of the hepatitis C virus;

(ii) materials required for polymerization of the nucleic acid from the 3′

-end of the oligonucleotide; and

(iii) a means for determining the presence of an oligonucleotide primer extended product.

101. The kit of claim 100, wherein the oligonucleotide probe is designed to identify cytidine at nucleotide 8443 of the RNA polymerase region of the hepatitis C virus.