Abstract
There are no available antivirals for many viruses or strains, while current antivirals are limited by toxicity and drug resistance. Therefore, alternative strategies, such as RNA interference (RNAi) are required. RNAi suppresses gene expression of any mRNA, making it an attractive candidate for antiviral therapeutics. Studies have evaluated siRNAs in a range of viruses, with some showing promising results. However, issues with stability and delivery of siRNAs remain. These issues may be minimized by modifying the siRNA structure, using an efficient delivery vector and targeting multiple regions of a virus's genome in a single dose. Finding these solutions could accelerate the progress of RNAi-based antivirals. This review highlights selected examples of antiviral siRNAs, limitations of RNAi and strategies to overcome these limitations
Keywords: RNAi, siRNAs, antiviral siRNAs, delivery vector, siRNA modification, combination siRNAs.
Graphical Abstract
[http://dx.doi.org/10.1016/j.addr.2016.03.005] [PMID: 27013255]
[http://dx.doi.org/10.1371/journal.pmed.0030242] [PMID: 16848617]
[http://dx.doi.org/10.1038/nrg3978] [PMID: 26281785]
[http://dx.doi.org/10.1186/s13073-015-0174-y] [PMID: 26019725]
[http://dx.doi.org/10.1038/35888] [PMID: 9486653]
[http://dx.doi.org/10.1007/s40265-018-0983-6] [PMID: 30251172]
[http://dx.doi.org/10.1038/s41392-020-0207-x] [PMID: 32561705]
[http://dx.doi.org/10.1038/mtna.2015.23] [PMID: 26372022]
[http://dx.doi.org/10.1002/rmv.1976] [PMID: 29656441]
[http://dx.doi.org/10.1126/science.286.5441.950] [PMID: 10542148]
[http://dx.doi.org/10.1101/gad.862301] [PMID: 11157775]
[http://dx.doi.org/10.1038/35053110] [PMID: 11201747]
[http://dx.doi.org/10.3389/fmicb.2018.02151] [PMID: 30254624]
[http://dx.doi.org/10.1016/S0140-6736(10)60357-1] [PMID: 20511019]
[http://dx.doi.org/10.1101/cshperspect.a007161] [PMID: 22474613]
[http://dx.doi.org/10.1128/CMR.00102-15] [PMID: 27281742]
[http://dx.doi.org/10.1186/s13613-016-0207-8] [PMID: 27813024]
[http://dx.doi.org/10.7883/yoken.JJID.2017.577] [PMID: 29709989]
[http://dx.doi.org/10.3892/etm.2017.4385] [PMID: 28587400]
[http://dx.doi.org/10.1371/journal.pone.0097231] [PMID: 24887060]
[http://dx.doi.org/10.1128/JVI.06338-11] [PMID: 22438545]
[http://dx.doi.org/10.3389/fonc.2018.00265] [PMID: 30116721]
[PMID: 19704168]
[http://dx.doi.org/10.3892/ol.2019.10543] [PMID: 31402935]
[http://dx.doi.org/10.1371/journal.pone.0096623] [PMID: 24794394]
[http://dx.doi.org/10.1007/s13337-018-00508-z] [PMID: 31179354]
[http://dx.doi.org/10.1016/j.jhep.2015.10.014] [PMID: 26505121]
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105948] [PMID: 32201353]
[http://dx.doi.org/10.3390/ijms21072657] [PMID: 32290293]
[http://dx.doi.org/10.3389/fbioe.2020.00916] [PMID: 32850752]
[http://dx.doi.org/10.1016/j.antiviral.2004.09.005] [PMID: 15652970]
[http://dx.doi.org/10.1038/nm1280] [PMID: 16116432]
[http://dx.doi.org/10.3390/molecules15107197] [PMID: 20956884]
[http://dx.doi.org/10.1385/MB:33:2:141] [PMID: 16757801]
[http://dx.doi.org/10.1016/j.jviromet.2007.05.017] [PMID: 17590445]
[http://dx.doi.org/10.1371/journal.pone.0034060] [PMID: 22457813]
[http://dx.doi.org/10.1128/JVI.05298-11] [PMID: 21795337]
[http://dx.doi.org/10.1261/rna.1268209] [PMID: 19324960]
[http://dx.doi.org/10.1136/bmj.l5140] [PMID: 31409588]
[http://dx.doi.org/10.1093/infdis/jir311]
[http://dx.doi.org/10.3390/pathogens5040066] [PMID: 27929449]
[http://dx.doi.org/10.1073/pnas.0437841100] [PMID: 12594334]
[http://dx.doi.org/10.1073/pnas.0402486101] [PMID: 15173599]
[http://dx.doi.org/10.3851/IMP2064] [PMID: 22311654]
[http://dx.doi.org/10.3390/v2071448] [PMID: 21994689]
[http://dx.doi.org/10.1126/scitranslmed.3009706] [PMID: 25143366]
[http://dx.doi.org/10.1172/JCI96185] [PMID: 29106386]
[http://dx.doi.org/10.1016/j.bjid.2015.05.008] [PMID: 26254692]
[http://dx.doi.org/10.1128/JVI.01557-08] [PMID: 18818323]
[http://dx.doi.org/10.1186/1471-2180-1-34] [PMID: 11801185]
[http://dx.doi.org/10.4161/rna.2.1.1198] [PMID: 17132935]
[http://dx.doi.org/10.1159/000445852] [PMID: 27403093]
[http://dx.doi.org/10.1038/mt.2012.226] [PMID: 23164935]
[http://dx.doi.org/10.1128/JVI.78.5.2601-2605.2004] [PMID: 14963165]
[http://dx.doi.org/10.1038/s41598-017-01819-9] [PMID: 28500326]
[http://dx.doi.org/10.1016/S1525-0016(03)00244-2] [PMID: 14599810]
[http://dx.doi.org/10.1016/j.drudis.2014.09.019] [PMID: 25281591]
[http://dx.doi.org/10.1038/nature14442] [PMID: 25901685]
[http://dx.doi.org/10.1186/1743-422X-9-275] [PMID: 23158906]
[http://dx.doi.org/10.1007/s12192-016-0747-8] [PMID: 27858224]
[http://dx.doi.org/10.1016/j.jconrel.2008.07.035] [PMID: 18727943]
[http://dx.doi.org/10.1016/j.jconrel.2014.03.048] [PMID: 24721235]
[http://dx.doi.org/10.1016/j.jconrel.2011.09.059] [PMID: 21930169]
[http://dx.doi.org/10.1038/mt.2011.207] [PMID: 21952167]
[http://dx.doi.org/10.1038/mtna.2016.24] [PMID: 27093170]
[http://dx.doi.org/10.1038/sj.gt.3302509] [PMID: 15750613]
[http://dx.doi.org/10.1016/j.jconrel.2014.12.042] [PMID: 25559178]
[http://dx.doi.org/10.1371/journal.pone.0135288] [PMID: 26407080]
[http://dx.doi.org/10.4081/idr.2011.2370] [PMID: 24470908]
[http://dx.doi.org/10.1038/mt.2009.271] [PMID: 19997090]
[http://dx.doi.org/10.1186/1742-4690-2-63] [PMID: 16232320]
[http://dx.doi.org/10.1038/sj.cgt.7701118] [PMID: 18157144]
[http://dx.doi.org/10.1038/s41598-017-00200-0] [PMID: 28273907]
[http://dx.doi.org/10.1007/s12033-016-9976-4] [PMID: 27766578]
[http://dx.doi.org/10.1038/nmat3765] [PMID: 24150415]
[http://dx.doi.org/10.1016/j.virol.2004.09.027] [PMID: 15527848]
[http://dx.doi.org/10.3389/fmed.2019.00109] [PMID: 31192211]
[http://dx.doi.org/10.1111/irv.12173] [PMID: 24215380]
[http://dx.doi.org/10.3389/fphar.2019.00444] [PMID: 31105570]
[http://dx.doi.org/10.3390/nano7040077] [PMID: 28379201]
[http://dx.doi.org/10.1111/cbdd.12993] [PMID: 28378934]
[http://dx.doi.org/10.1002/0471142700.nc1603s39]
[http://dx.doi.org/10.1016/S1773-2247(12)50007-9]
[http://dx.doi.org/10.1371/journal.pone.0174523] [PMID: 28380007]
[http://dx.doi.org/10.7150/oncm.25785]
[http://dx.doi.org/10.1080/10717544.2018.1543366] [PMID: 30799658]
[http://dx.doi.org/10.3390/md17060381] [PMID: 31242678]
[http://dx.doi.org/10.1111/j.1742-4658.2010.07904.x] [PMID: 21078116]
[http://dx.doi.org/10.1039/C1NR11188D] [PMID: 22076024]
[http://dx.doi.org/10.1016/j.ejps.2010.03.019] [PMID: 20359532]
[http://dx.doi.org/10.1146/annurev-bioeng-071813-105119] [PMID: 24905873]
[http://dx.doi.org/10.1134/S0006297916070063] [PMID: 27449616]
[http://dx.doi.org/10.1126/science.aan4672] [PMID: 29326244]
[http://dx.doi.org/10.1038/s41375-018-0106-0] [PMID: 29654266]
[http://dx.doi.org/10.3390/v10010008] [PMID: 29280961]
[http://dx.doi.org/10.1002/jgm.3097] [PMID: 31069898]
[http://dx.doi.org/10.1167/iovs.16-20303] [PMID: 27893109]
[http://dx.doi.org/10.1089/nat.2012.0371] [PMID: 22913596]
[http://dx.doi.org/10.1016/j.ekir.2017.03.016] [PMID: 29270490]
[http://dx.doi.org/10.1007/s11095-017-2134-2] [PMID: 28389707]