Comb shaped antivirals ending with or without chain terminating bases
View Patent ↗Modified antisense mucleic acid molecules ending with or without chain terminating bases targeting the HIV-1 viral genomic RNA 3′ LTR region, and uses thereof for inhibiting HIV-1 replication and infection, are disclosed. The antisense mucleic acid molecules more specifically target a sequence corresponding to about nucleotide 9628 to about nucleotide 9642 of HIV-1 clone pNL4-3.
1 . Antisense nucleic acid molecules directed against a sequence corresponding to nucleotide 9628 to nucleotide 9642 of HIV-1 clone pNL4-3 ending with or without a 3′ terminal ddC and comprising one of the following sequences (I) or (II):
(I) 5′-A*fC*GG*GfC*AfC*AfC*AC*T*+A*C-3′ (SEQ ID NO: 1)
(II) 5′-A*fC*GG*GfC*AfC*AfC*AC*T*+A*[ddC]-3′ (SEQ ID NO: 2);
wherein “+N” denotes a bridged nucleic acid nucleotide wherein “N” is “A,” “C,” “G” or “T”, “*” denotes a phosphorothioate linkage, “fN” denotes a 2′-fluoro ribonucleotide, and “[ddC]” denotes a 2′,3′-dideoxycytidine at the 3′ terminus.
2 . A pharmaceutical composition comprising the antisense nucleic acid molecules of claim 1 , an excipient, and/or a cell delivery agent.
3 . The pharmaceutical composition of claim 2 , wherein the antisense nucleic acid molecule is SEQ ID NO: 1.
4 . The pharmaceutical composition of claim 2 , wherein the antisense nucleic acid molecule is SEQ ID NO: 2.
5 . A method of designing an antisense oligomer to target HIV-1 genomic RNA, comprising (i) identifying, in an HIV-1 strain, the sequence corresponding to nucleotides 9628-9642 of HIV-1 clone pNL4-3; and (ii) adapting the sequence of an antisense nucleic acid molecule according to claim 1 , wherein the molecule has a chain-terminating base at the 3′ end, to be complementary to the identified sequence.
6 . A method of using the antisense nucleic acid molecules of claim 1 , comprising administering to a subject in need thereof an effective amount of the antisense nucleic acid molecule of claim 1 , wherein the molecule hybridizes to an accessible sequence at a 3′ or 5′ LTR region of the HIV-1 clone pNL4-3.
7 . A method of treating HIV-1 infection using the antisense nucleic acid molecule of claim 1 , comprising administering to a subject in need thereof a therapeutically effective amount of the molecule.
8 . A method for treating an HIV-1 infection in a subject, comprising administering to the subject an effective amount of (a) the antisense nucleic acid molecule of claim 1 or (b) a pharmaceutical composition comprising the antisense nucleic acid molecule and an excipient, and/or a cell delivery agent.
9 . The method of claim 8 , wherein the antisense nucleic acid molecule comprises a 3′ chain-terminating ddC.
10 . The method of claim 8 , wherein the antisense nucleic acid molecule is SEQ ID NO: 1.
11 . The method of claim 8 , wherein the antisense nucleic acid molecule is SEQ ID NO: 2.
12 . The method of claim 8 , wherein the pharmaceutical composition comprises the antisense nucleic acid molecule SEQ ID NO: 2, an excipient, and a cell delivery agent.