RNase L activators and antisense oligonucleotides effective to treat RSV infections
First Claim
1. A composition comprising:
- a) an oligonucleotide, comprising at least one 2′
O methyl nucleotide, in which the oligonucleotide is complementary to between 15 and 20 nucleotides of a conserved gene-start or gene-end-signal of a genomic RNA strand of a Respiratory Syncytial Virus and a terminus of the oligonucleotide is attached to a linker; and
b) an activator of RNase L attached to the linker.
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Abstract
The present invention relates to methods of inhibiting infection by RNA viruses with complexes of an activator of RNase L and an oligonucleotide that is capable of binding to the genome, antigenome or mRNAs of a negative strand RNA virus to specifically cleave the genomic or antigenomic RNA strand of the virus. In accordance with the present invention, the methods and complexes of the invention may be applied to target any negative strand RNA virus. The invention in one embodiment relates to a covalently linked complex of an oligonucleotide that is capable of binding to the genomic or antigenomic template RNA strand of a negative strand RNA virus and/or binding to an mRNA of a viral protein (an “antisense oligonucleotide”) coupled to an activator of RNase L. In a preferred embodiment of the present invention, the oligonucleotide component of the complex is complementary to a region of the viral genomic RNA strand characterized by repeated or consensus sequences.
170 Citations
15 Claims
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1. A composition comprising:
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a) an oligonucleotide, comprising at least one 2′
O methyl nucleotide, in which the oligonucleotide is complementary to between 15 and 20 nucleotides of a conserved gene-start or gene-end-signal of a genomic RNA strand of a Respiratory Syncytial Virus and a terminus of the oligonucleotide is attached to a linker; and
b) an activator of RNase L attached to the linker. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A method of inhibiting Respiratory Syncytial Viral (RSV) infection in a mammalian cell infected with RSV which comprises a step of providing an amount of a complex effective to inhibit RSV infection, said complex comprising:
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a) an antisense oligonucleotide, in which the sequence of said oligonucleotide is complementary to between 15 and 20 nucleotides of a conserved region of the genomic RNA strand of a strain of a Respiratory Syncytial Virus and a terminus of the oligonucleotide is attached to a linker; and
b) an activator of RNase L attached to the linker. - View Dependent Claims (12)
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11. A method of inhibiting Respiratory Syncytial Viral (RSV) infection in a mammalian cell infected with RSV which comprises a step of providing an amount of a complex effective to inhibit RSV infection, said complex comprising:
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a) an antisense oligonucleotide, having a hydroxyl moiety at a first end, in which the sequence of said oligonucleotide is complementary to between about 15 and 20 nucleotides of a normally single stranded portion of the genomic RNA strand of a strain of a Respiratory Syncytial Virus and a terminus of the oligonucleotide is attached to a linker;
b) an activator of RNase L attached to the linker; and
c) a pharmaceutically acceptable, aerosolizable carrier.
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13. A composition to inhibit RSV infection in a mammalian cell comprising:
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a) an effective concentration of an oligonucleotide, wherein the oligonucleotide comprising at least one 2′
O-methyl modified nucleotide, is between 15 and 20 nucleotides of complementary sequence to a conserved gene-start or gene-end signal of a Respiratory Syncytial Virus genomic RNA strand and is attached to a RNase L activator by a linker; and
b) a pharmaceutically acceptable carrier. - View Dependent Claims (14, 15)
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Specification