Antiviral agents
An antiviral agent is provided, having a phosphorodiamidate morpholino oligomer with an antisense sequence to a portion of a genome of a strain of Zika virus (ZIKV). The antiviral agent finds many uses, such as in a pharmaceutical composition, a method of treating ZIKV-mediated disease, a method of preventing ZIKV-mediated disease, a method of reducing or preventing the replication of ZIKV in a host cell, a method of controlling the spread of ZIKV in donated tissue, a treated tissue sample, and in the manufacture of a medicament for the treatment or prevention or ZIKV-mediated disease.
1. An antiviral agent that restricts the replication of Zika virus (ZIKV) in a cell, the agent comprising a phosphorodiamidate morpholino oligomer (PMO) comprising a sequence of 5′-CAT GAC CAG AAA CTC TCG TTT CCA A-3′ (SEO ID NO: 3) or 5′-CAT GGA GTC TCT GGT CTT TCC CAG C-3′ (SEQ ID NO: 5).
2. A pharmaceutical composition for the treatment or prevention of a disease mediated by the Zika virus (ZIKV), the composition comprising: the antiviral agent of claim 1 and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2 , wherein the antiviral agent is present in a therapeutically effective amount.
4. The pharmaceutical composition of claim 3 , wherein the therapeutically effective amount is sufficient to provide the agent at a concentration of at least about 10 μM at a site of viral infection in a subject.
5. The pharmaceutical composition of claim 3 , wherein the therapeutically effective amount is a nontoxic amount.
6. The pharmaceutical composition of claim 3 , wherein the therapeutically effective amount is sufficient to provide the agent at a dosage/body mass concentration of up to an amount selected from: 0.05, 0.1, 0.15, 0.2, 0.3, 0.5, 1, 1.5, 2, 3, 5, 10, 15, 20, 30 mg/kg, about any of the foregoing values, and a range between any of the foregoing values.
7. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is formulated to deliver the antiviral agent to: a circulatory system, a placenta, a fetus, an eye, a kidney, a brain, a skin, one or more testes, one or more neurons, one or more stem cells, a vagina, a spleen, an auditory system, or any combination of the foregoing, of a subject.
8. A method of treatment or prevention of a disease mediated by the Zika virus (ZIKV) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 2 .
9. The antiviral agent of claim 1 , wherein when the sequence comprises 5′-CAT GAC CAG AAA CTC TCG TTT CCA A-3′ (SEQ ID NO: 3), the antiviral agent targets a sequence in the 5′ region of the ZIKV virus.
10. The antiviral agent of claim 1 , wherein when the sequence comprises 5′-CAT GAC CAG AAA CTC TCG TTT CCA A-3′ (SEO ID NO: 3), the sequence hybridizes under physiological conditions with RNA containing the sequence 5′-TTG GAA ACG AGA GTT TCT GGT CAT G-3′ (SEQ ID NO: 2).
11. The antiviral agent of claim 1 , wherein when the sequence comprises 5′-CAT GGA GTC TCT GGT CTT TCC CAG C-3′ (SEQ ID NO: 5), the antiviral agent targets a sequence in the 3′ region of the ZIKV virus.
12. The antiviral agent of claim 1 , wherein when the sequence comprises 5′-CAT GGA GTC TCT GGT CTT TCC CAG C-3′ (SEQ ID NO: 5) the sequence hybridizes under physiological conditions with RNA containing the sequence 5′-GCT GGG AAA GAC CAG AGA CTC CAT G-3′ (SEQ ID NO: 4).
13. The antiviral agent of claim 1 , wherein the agent comprises a moiety for intracellular delivery.
14. The antiviral agent of claim 1 , wherein the agent comprises an octa-guanidine dendrimer delivery moiety.
15. The antiviral agent of claim 1 , wherein the agent comprises an octa-guanidine dendrimer of the following structure:
16. The pharmaceutical composition of claim 2 , wherein the disease mediated by ZIKV is selected from the group consisting of: Zika fever, Guillain-Barre syndrome, a congenital defect, microcephaly, ocular disease, and Zika associated organ pathology.
17. The pharmaceutical composition of claim 3 , wherein the therapeutically effective amount is sufficient to provide the agent at a concentration of below an LD50 for a subject.
18. The antiviral agent of claim 9 , wherein the 5′ region of the ZIKV virus comprises a 5′ untranslated region.
19. The antiviral agent of claim 11 wherein the 3′ region of the ZIKV virus comprises a 3′ untranslated region.
20. The antiviral agent of claim 11 , wherein the 3′ region of the ZIKV virus comprises a 3′ short hairpin structure.