Hyperstabilizing antisense nucleic acid binding agents
AssigneeBoard of Supervisors of Louisana State University and Agricultural and Mechanical College
InventorDavid H. Swenson
Life of this patent
Estimating the term…
Abstract
Attaching certain ligands to antisense probes will hyperstabilize sense-antisense duplexes. Such a hyperstabilized duplex is resistant to melting of the strands from one another, to unwinding of the strands, and to the action of nucleases. Applications include antiretroviral action, antireverse-transcriptase action, antiviral action, antiparasitical action, antibacterial action, antifungal action, anticancer action, anti-oncogene action, and other applications where it is desired to inhibit gene expression at the genomic or messenger RNA level. The preferred ligands are certain minor-groove-binding agents, exemplified by CC-1065 and synthetic CC-1065 analogs.
Claims53
A composition for binding a selected ribonucleic acid sequence which is not a homopolymer, comprising:
- (a) an oligonucleotide which is not a homopolymer, and which is complementary to the a selected ribonucleic acid sequence which is not a homopolymer, and which can base-pair to the selected ribonucleic acid sequence to form a double helix having a minor groove and a major groove;
- and
- (b) a non-alkylating binding agent which preferentially binds in the minor groove of a double helix formed by the base-pairing of said oligonucleotide and the selected ribonucleic acid sequence, and which increases the strand separation temperature of the double helix;
- wherein said binding agent is selected from the group consisting of CC-1065, tristabilin, an agent comprising a pyrrolomethoxy hydroxyindole from two to four pyrrolomethoxyhydroxyindole tricyclic ring, U71,184, an indole, an indole rings, an agent comprising from two to four indoles, an agent comprising from two to four indoles substituted with at least one hydroxy group, an indole agent comprising from two to four indoles substituted with at least one methoxy group, an indole and an agent comprising from two to four indoles substituted with at least one pyrrole, and a lexitropsin .
A composition for binding a selected ribonucleic acid sequence which is not a homopolymer, comprising:
- (a) an oligonucleotide which is not a homopolymer, and which is complementary to the selected ribonucleic acid sequence, and which can base-pair to the selected ribonucleic acid sequence to form a double helix having a minor groove and a major groove;
- and
- (b) a binding agent which preferentially binds in the minor groove of a double helix formed by the base-pairing of said oligonucleotide and the selected ribonucleic acid sequence, and which increases the strand separation temperature of the double helix, wherein said binding agent is chemically tethered to said oligonucleotide.
An in vitro method for binding a selected ribonucleic acid sequence which is not a homopolymer, comprising the steps of:
- (a) contacting the selected ribonucleic acid sequence in vitro with an oligonucleotide which is not a homopolymer, and which is complementary to the selected ribonucleic acid sequence, and which can base-pair to the selected ribonucleic acid sequence to form a double helix having a minor groove and a major groove, until such a double helix is formed;
- and
- (b) contacting the double helix in vitro with a non-alkylating binding agent which preferentially binds in the minor groove of the double helix, and which increases the strand separation temperature of the double helix, until said binding agent has bound in the minor groove;
- wherein the binding agent is selected from the group consisting of tristabilin, an agent comprising from two to four pyrrolomethoxyhydroxyindole tricyclic rings, an agent comprising from two to four indoles, an agent comprising from two to four indoles substituted with at least one hydroxy group, an agent comprising from two to four indoles substituted with at least one methoxy group, and an agent comprising from two to four indoles substituted with at least one pyrrole.
A composition of matter comprising tristabilin.
Dependencies are inferred from the claim text.