Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.
Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.
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DOI：
10.1038/s41591-022-01908-x
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发表时间：
2022-09
期刊：
影响因子：
82.9
通讯作者：
Glenn, Jeffrey S.
中科院分区：
文献类型：
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作者：
Hagey, Rachel J.;Elazar, Menashe;Pham, Edward A.;Tian, Siqi;Ben-Avi, Lily;Bernardin-Souibgui, Claire;Yee, Matthew F.;Moreira, Fernando R.;Rabinovitch, Meirav Vilan;Meganck, Rita M.;Fram, Benjamin;Beck, Aimee;Gibson, Scott A.;Lam, Grace;Devera, Josephine;Kladwang, Wipapat;Nguyen, Khanh;Xiong, Anming;Schaffert, Steven;Avisar, Talia;Liu, Ping;Rustagi, Arjun;Fichtenbaum, Carl J.;Pang, Phillip S.;Khatri, Purvesh;Tseng, Chien-Te;Taubenberger, Jeffery K.;Blish, Catherine A.;Hurst, Brett L.;Sheahan, Timothy P.;Das, Rhiju;Glenn, Jeffrey S.
甲型流感病毒（IAV）频繁的基因变化对疫苗策略提出了挑战，并产生了对当前药物的耐药性。我们试图鉴定IAV基因组中保守的和必需的RNA二级结构，这些结构预测对治疗靶向的突变有更大的限制。我们鉴定并遗传验证了介导体外包装和体内疾病的RNA结构（PSL 2），并且在所有已知的IAV分离株中是保守的。在致死IAV接种物后3天或前14天给予靶向PSL 2的锁核酸（LNA）在小鼠中提供100%存活，导致对用10倍致死接种物再攻击的强免疫力的发展，避免了选择抗性的尝试，并保留了针对神经氨酸酶抑制剂（NAI）抗性病毒的全部效力。使用靶向SARS-CoV-2的类似方法，预防性给予对病毒基因组中高度保守的RNA结构具有特异性的LNA，保护仓鼠免受SARS-CoV-2 USA_WA1/2020变体的有效传播。这些发现强调了这种方法通过我们称之为“可编程抗病毒药物”的过程对任何感兴趣的病毒的潜在适用性，并对抗病毒预防和暴露后治疗产生影响。
Influenza A virus (IAV)’s frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV’s genome predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated a RNA structure (PSL2) that mediates in vitro packaging and in vivo disease, and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA) administered 3 days after, or 14 days before, a lethal IAV inoculum provided 100% survival in mice, lead to the development of strong immunity to rechallenge with a ten-fold lethal inoculum, evaded attempts to select for resistance, and retained full potency against neuraminidase inhibitor (NAI)-resistant virus. Using an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term “programmable antivirals”, with implications for antiviral prophylaxis and post-exposure therapy.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
影响因子：
14.9
作者：
Pang PS;Elazar M;Pham EA;Glenn JS
通讯作者：
Glenn JS
DOI：
10.1093/bioinformatics/btp250
发表时间：
2009-08-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Darty K;Denise A;Ponty Y
通讯作者：
Ponty Y
影响因子：
3.7
作者：
Priore SF;Moss WN;Turner DH
通讯作者：
Turner DH
影响因子：
21.8
作者：
通讯作者：
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