Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models
Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models
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DOI：
10.1128/jvi.02360-06
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发表时间：
2007-06-01
影响因子：
5.4
通讯作者：
Buchmeier, Michael J.
中科院分区：
文献类型：
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作者：
Burrer, Renaud;Neuman, Benjamin W.;Buchmeier, Michael J.
最近出现的新型致病性人类和动物冠状病毒突出了对有效对抗这些病毒谱的抗病毒疗法的需求。我们已经使用了几种小鼠肝炎病毒（MHV）株在细胞培养和在小鼠模型中的体内研究肽缀合的反义磷酰二胺吗啉寡聚体（P-PMO）的抗病毒特性。在细胞培养物中测试了针对病毒基因组中不同靶位点的10种P-PMO，其中一种（5 TERM）与基因组RNA的5'末端互补，对6种MHV株有效。用与5 TERM PMO序列缀合的各种富含精氨酸的肽进行进一步的研究，以评价功效和毒性，从而选择用于体内测试的候选物。在未感染的小鼠中，延长P-PMO治疗不会导致体重减轻或可检测到的组织病理学变化。5 TERM P-PMO处理降低了靶器官中的病毒滴度，并保护小鼠免受病毒诱导的组织损伤。在大多数实验条件下，预防性5 TERM P-PMO治疗降低了与感染相关的体重减轻量。治疗还延长了两种致死性攻击模型的存活时间。在某些情况下，高剂量的病毒接种，然后延迟治疗，5 TERM P-PMO治疗是没有保护性的，并在治疗组的发病率增加，这表明P-PMO可能会导致在未感染的动物中不明显的患病小鼠的毒性作用。然而，观察到的强抗病毒作用表明，随着进一步的发展，P-PMO可能提供一种有效的治疗方法来对抗广泛的冠状病毒感染。
The recent emergence of novel pathogenic human and animal coronaviruses has highlighted the need for antiviral therapies that are effective against a spectrum of these viruses. We have used several strains of murine hepatitis virus (MHV) in cell culture and in vivo in mouse models to investigate the antiviral characteristics of peptide-conjugated antisense phosphorodiamidate morpholino oligomers (P-PMOs). Ten P-PMOs directed against various target sites in the viral genome were tested in cell culture, and one of these (5TERM), which was complementary to the 5' terminus of the genomic RNA, was effective against six strains of MHV. Further studies were carried out with various arginine-rich peptides conjugated to the 5TERM PMO sequence in order to evaluate efficacy and toxicity and thereby select candidates for in vivo testing. In uninfected mice, prolonged P-PMO treatment did not result in weight loss or detectable histopathologic changes. 5TERM P-PMO treatment reduced viral titers in target organs and protected mice against virus-induced tissue damage. Prophylactic 5TERM P-PMO treatment decreased the amount of weight loss associated with infection under most experimental conditions. Treatment also prolonged survival in two lethal challenge models. In some cases of high-dose viral inoculation followed by delayed treatment, 5TERM P-PMO treatment was not protective and increased morbidity in the treated group, suggesting that P-PMO may cause toxic effects in diseased mice that were not apparent in the uninfected animals. However, the strong antiviral effect observed suggests that with further development, P-PMO may provide an effective therapeutic approach against a broad range of coronavirus infections.