Antisense antiviral compound and method for treating arenavirus infection
View Patent ↗The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Arenaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of Arenavirus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides have a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with viral RNA sequences within a 19 nucleotide region of the 5′-terminal regions of the viral RNA, viral complementary RNA and/or mRNA identified by SEQ ID NO:1.
1. An antisense oligonucleotide compound comprised of morpholino subunits and phosphorous-containing intersubunit linkages having the following structure (I):
wherein:
Y 1 ═O;
Z═O;
Pi and Pj are independently a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide;
X is alkyl, alkoxy, thioalkoxy, amino, alkyl amino, dialkylamino or piperazynyl; and
wherein the antisense oligonucleotide compound:
(i) comprises at least one phosphorous-containing intersubunit linkage wherein X is piperazynyl;
(ii) contains between 12-40 base-pairing moieties;
(iii) comprises a targeting sequence of at least 12 contiguous base-pairing moieties complementary to SEQ ID NO:1; and
(iv) optionally comprises a hydrophilic polymer for enhancing the solubility of the antisense oligonucleotide compound; and
wherein the antisense oligonucleotide compound is capable of binding to vRNA/vcRNA or mRNA strands of an Arenavirus in the Arenaviridae family to form a heteroduplex structure having a Tm of dissociation of at least 45° C.
2. The antisense oligonucleotide compound of claim 1 , wherein X is dimethylamino when X is not piperazynyl.
3. The antisense oligonucleotide compound of claim 1 , wherein X in at least 80% of the phosphorous-containing intersubunit linkages is not piperazynyl.
4. The antisense oligonucleotide compound of claim 1 , wherein the antisense oligonucleotide compound contains between 14-24 base-pairing moieties.
5. The antisense oligonucleotide compound of claim 1 , wherein the antisense oligonucleotide compound comprises a targeting sequence of 19 contiguous base-pairing moieties complementary to SEQ ID NO:1.
6. The antisense oligonucleotide compound of claim 1 , wherein the antisense oligonucleotide compound comprises a polyethyleneglycol moiety for enhancing the solubility of the antisense oligonucleotide compound.
7. A composition comprising the antisense oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
8. The antisense oligonucleotide compound of claim 4 , wherein the targeting sequence has 20 base-pairing moieties.