Details for Patent: 8,759,307

Title:	Oligonucleotide compound and method for treating nidovirus infections
Abstract:	A method and oligonucleotide compound for inhibiting replication of a nidovirus in virus-infected animal cells are disclosed. The compound (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the infected cells, (iii) contains between 8-25 nucleotide bases, and (iv) has a sequence capable of disrupting base pairing between the transcriptional regulatory sequences in the 5' leader region of the positive-strand viral genome and negative-strand 3' subgenomic region. In practicing the method, infected cells are exposed to the compound in an amount effective to inhibit viral replication.
Inventor(s):	Stein; David A. (Corvallis, OR), Bestwick; Richard K. (Corvallis, OR), Iversen; Patrick L. (Corvallis, OR), Neuman; Benjamin (Encinitas, CA), Buchmeier; Michael (Encinitas, CA), Weller; Dwight D. (Corvallis, OR)
Assignee:	Sarepta Therapeutics, Inc. (Corvallis, OR) The Scripps Research Institute (La Jolla, CA)
Filing Date:	Apr 25, 2008
Application Number:	12/109,856
Claims:	1. An antisense compound, which is composed of morpholino subunits and phosphorus-containing intersubunit linkages, which join a morpholino nitrogen of one subunit to a 5' exocyclic carbon of an adjacent subunit, for use in inhibiting replication of a nidovirus in mammalian host cells, comprising: (i) a nuclease-resistant backbone, (ii) 12-25 nucleotide bases, and (iii) a targeting sequence that is complementary to at least 12 contiguous bases contained in SEQ ID NO: 3; wherein the targeting sequence forms a heteroduplex structure composed of SEQ ID NO: 3 and the antisense compound, SEQ ID NO:3 comprising a transcriptional regulatory sequence in a 5' leader region of a positive-strand viral genome, the heteroduplex structure characterized by a T.sub.m, of dissociation of at least 45.degree. C., wherein the heteroduplex structure disrupts base pairing between the transcriptional regulatory sequence in the 5' leader region of the positive-strand viral genome and a negative-strand 3' subgenomic region, thereby inhibiting viral replication. 2. The compound of claim 1, in which at least 2 and no more than half of the total number of intersubunit linkages are cationic linkages. 3. The compound of claim 2, wherein said morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure: ##STR00002## where Y.sub.1.dbd.O, Z.dbd.O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X for the uncharged linkages is alkyl, alkoxy, thioalkoxy, or an alkyl amino of the form wherein NR.sub.2, where each R is independently hydrogen or methyl, and for the positively charged linkages, X is 1-piperazine. 4. The compound of claim 1, which contains a sequence selected from the group consisting of SEQ ID NOS: 22 and 23. 5. The compound of claim 1, wherein the compound is conjugated to an Arg-rich peptide. 6. The compound of claim 5, wherein the peptide is SEQ ID NO: 47. 7. The compound of claim 1, in which the intersubunit linkages are uncharged. 8. The compound of claim 7, wherein the morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure: ##STR00003## where Y.sub.1.dbd.O, Z.dbd.O, Pj is a purine or pyrimidine base pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, amino or alkyl amino, including dialkylamino.