Antiviral agents

Abstract

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.

We claim: 
     
       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 consisting of an antisense 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 antisense 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 antisense 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. 
     
     
       21. The antiviral agent of  claim 1 , wherein the antisense sequence is 5′-CAT GGA GTC TCT GGT CTT TCC CAG C-3′ (SEQ ID NO: 5).