NEUROPROTECTIVE MOLECULES AND METHODS OF TREATING NEUROLOGICAL DISORDERS AND INDUCING STRESS GRANULES
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Abstract
Provided herein are neuroprotective molecules containing a sequence of 25-35 contiguous nucleotides that is at least 80% identical to a contiguous sequence between nucleotide 1 and nucleotide 50 of a mature human tRNA and at least four contiguous guanosine-containing nucleotides, where the sequence of 25-35 contiguous nucleotides contains a D-loop stem structure, the at least four contiguous guanosine-containing nucleotides are located at the 5′ end of the neuroprotective molecule, and the neuroprotective molecule contains at least one deoxyribonucleotide. Also provided are neuroprotective molecules containing a sequence of 25-35 contiguous nucleotides that is at least 80% identical to a contiguous sequence between nucleotide 1 and nucleotide 50 of a mature human tRNA selected from the group of tRAArg, tRNAAsp, tRNAGln, tRNAGlu, tRNAGly, tRNAHis, tRNAIle, tRNALeu, tRNALys, tRNAMet, tRNAPro, tRNASeC, tRNASer, tRNASup, tRNAThr, tRNATrp, tRNATyr, tRNAVal, tRNAAsn, and tRNAPhe; and at least four contiguous guanosine-containing nucleotides, where the sequence of 25-35 contiguous nucleotides contains a D-loop stem structure and the at least four contiguous guanosine-containing nucleotides are located at the 5′ end of the neuroprotective molecule. Also provided are methods of inducing or increasing stress granule formation in a cell, decreasing protein translation in a cell, decrease stress-induced cell death, or treating a neurological disorder associated with neuron death in a subject using at least one of these neuroprotective molecules or a C-myc oligonucleotide. Also provided are methods of identifying a candidate translation.
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Citations
46 Claims
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1-22. -22. (canceled)
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23. A neuroprotective molecule consisting of:
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(i) a sequence of 25-35 contiguous nucleotides that is at least 90% identical to a contiguous sequence between nucleotide 1 and nucleotide 50 of a mature human transfer ribonucleic acid (tRNA) having a sequence selected from the group consisting of SEQ ID NOs;
4, 10, 32, 37, 40-46, 48-55, and 58-62, wherein a first nucleotide of the 25-35 contiguous nucleotides corresponds to nucleotide position 1 of the mature human tRNA sequence;
at least part of the sequence of 25-35 contiguous nucleotides forms a D-loop stem structure;(ii) optionally a 5′
monophosphate, one or more modified nucleotides, and/or one or more modifications in a phosphate backbone in the nucleotide(s) in (i) of the neuroprotective molecule; and(iii) optionally a 5′
-protective group and/or a 3′
-protective group;wherein at least four contiguous nucleotides in (i) of the neuroprotective molecule at the 5′
-end are guanosine deoxyribonucleotides; and
the neuroprotective molecule is capable of decreasing protein translation in a rabbit reticulocyte assay. - View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31)
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32. A neuroprotective molecule consisting of:
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(i) a sequence of 25-35 contiguous nucleotides that is at least 90% identical to a contiguous sequence between nucleotide 1 and nucleotide 50 of mature human tRNAAla or mature human tRNACys, wherein a first nucleotide of the 25-35 contiguous nucleotides corresponds to nucleotide position 1 of the mature human tRNA sequence;
at least part of the sequence of 25-35 contiguous nucleotides forms a D-loop stem structure; and
at least part of the sequence of 25-35 contiguous nucleotides binds to YB-1;(ii) optionally a 5′
-monophosphate, one or more modified nucleotides, and/or one or more modifications in a phosphate backbone of the nucleotide(s) in (i) of the neuroprotective molecule; and(iii) optionally a 5′
-protective group and/or a 3′
-protective group;wherein at least four contiguous nucleotides in (i) of the neuroprotective molecule at the 5′
-end are guanosine deoxyribonucleotides;
the neuroprotective molecule binds YB-1; and
the neuroprotective molecule is capable of decreasing protein translation in a rabbit reticulocyte assay. - View Dependent Claims (33, 34, 35, 36, 37, 38)
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39. A neuroprotective molecule consisting of:
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(i) a sequence of 25-35 contiguous nucleotides that is at least 90% identical to a contiguous sequence between nucleotide 1 and nucleotide 50 of a mature human transfer ribonucleic acid (tRNA) having the sequence SEQ ID NOs;
47, wherein a first nucleotide of the 25-35 contiguous nucleotides corresponds to nucleotide position 1 of the mature human tRNA sequence;
at least part of the sequence of 25-35 contiguous nucleotides forms a D-loop stem structure;(ii) at least four contiguous guanosine-containing nucleotides at the 5′
-end of (i);(iii) optionally a 5′
monophosphate, one or more modified nucleotides, and/or one or more modifications in a phosphate backbone in the nucleotide(s) in (i) of the neuroprotective molecule; and(iv) optionally a 5′
-protective group and/or a 3′
-protective group;wherein the at least four contiguous nucleotides in (ii) are guanosine deoxyribonucleotides; and
the neuroprotective molecule is capable of decreasing protein translation in a rabbit reticulocyte assay. - View Dependent Claims (40, 41, 42, 43, 44, 45, 46)
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Specification