Coronaviruses - drug discovery and therapeutic options.
Coronaviruses - drug discovery and therapeutic options.
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DOI：
10.1038/nrd.2015.37
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Yuen KY
中科院分区：
文献类型：
--
作者：
Zumla A;Chan JF;Azhar EI;Hui DS;Yuen KY
严重急性呼吸系统综合征（SARS）和中东呼吸综合征（MERS）是能够人际传播的新型人畜共患冠状病毒感染的例子，可导致大规模流行，对患者健康和社会经济因素产生重大影响。与其他人类致病性冠状病毒引起的轻度疾病患者不同，感染SARS或MERS冠状病毒的患者可能会出现严重的急性呼吸系统疾病，并伴有多器官衰竭。SARS和MERS的病死率分别约为10%和35%。SARS和MERS都给临床管理带来了重大挑战，因为在随机临床试验中，没有特定的抗病毒治疗被证明对这两种感染有效。人们正在努力发现治疗冠状病毒感染的新药物。基于病毒的治疗包括针对病毒刺突糖蛋白的单克隆抗体和抗病毒肽，病毒酶抑制剂，病毒核酸合成抑制剂以及其他病毒结构和辅助蛋白的抑制剂。基于宿主的治疗包括增强干扰素反应或影响参与病毒复制的宿主信号通路或冠状病毒用于病毒复制的宿主因子的药物。新型抗冠状病毒药物临床开发面临的主要挑战包括：用于评估SARS和中东呼吸综合征潜在治疗方法的合适动物模型数量有限、目前没有新的SARS病例、中东呼吸综合征病例数量有限——这些病例在地理上也主要局限于中东地区——以及缺乏针对其他致病性较低的冠状病毒引起的轻度感染开发抗病毒药物的行业激励措施。中东呼吸综合征冠状病毒在发现3年后仍对全球健康构成威胁，这为解决目前开发新型抗冠状病毒药物方面的障碍提供了一个黄金机会。应该形成一个由临床医生、病毒学家和药物开发人员组成的组织良好的多学科国际合作网络，再加上政治承诺，使用已经在体外和/或动物模型中被证明安全有效的抗冠状病毒药物，特别是洛匹那韦-利托那韦、干扰素β -1b和针对病毒刺突糖蛋白的单克隆抗体和抗病毒肽，开展临床试验。本文的在线版本（doi:10.1038/nrd.2015.37）包含补充材料，授权用户可使用。由冠状病毒引起的严重急性呼吸系统综合症（SARS）和中东呼吸系统综合症（MERS）因其高死亡率和可能引起流行病而引起了广泛关注。Yuen和他的同事讨论了这些综合征的治疗方案的进展，包括针对病毒和宿主的药物，以及在进一步开发中需要克服的挑战。本文的在线版本（doi:10.1038/nrd.2015.37）包含补充材料，授权用户可使用。在人类中，感染人类冠状病毒（HCoV）毒株HCoV- 229e、HCoV- oc43、HCoV- nl63和HCoV- hku1通常会导致轻度、自限性上呼吸道感染，如普通感冒。相比之下，分别于2003年在中国香港和2012年在沙特阿拉伯发现的导致严重急性呼吸综合征（SARS）和中东呼吸综合征（MERS）的冠状病毒，由于能够在人群中引起社区和卫生保健相关的严重感染暴发，在过去12年中受到了全球的关注。这两种病毒给临床管理带来了重大挑战，因为没有特定的抗病毒药物可用。本文综述了SARS和MERS的流行病学、病毒学、临床特点和目前的治疗策略，并讨论了基于病毒和基于宿主的新型冠状病毒感染治疗方案的发现和发展。本文的在线版本（doi:10.1038/nrd.2015.37）包含补充材料，授权用户可使用。
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are examples of emerging zoonotic coronavirus infections capable of person-to-person transmission that result in large-scale epidemics with substantial effects on patient health and socioeconomic factors. Unlike patients with mild illnesses that are caused by other human-pathogenic coronaviruses, patients with SARS or MERS coronavirus infections may develop severe acute respiratory disease with multi-organ failure. The case–fatality rates of SARS and MERS are approximately 10% and 35%, respectively. Both SARS and MERS pose major clinical management challenges because there is no specific antiviral treatment that has been proven to be effective in randomized clinical trials for either infection. Substantial efforts are underway to discover new therapeutic agents for coronavirus infections. Virus-based therapies include monoclonal antibodies and antiviral peptides that target the viral spike glycoprotein, viral enzyme inhibitors, viral nucleic acid synthesis inhibitors and inhibitors of other viral structural and accessory proteins. Host-based therapies include agents that potentiate the interferon response or affect either host signalling pathways involved in viral replication or host factors utilized by coronaviruses for viral replication. The major challenges in the clinical development of novel anti-coronavirus drugs include the limited number of suitable animal models for the evaluation of potential treatments for SARS and MERS, the current absence of new SARS cases, the limited number of MERS cases — which are also predominantly geographically confined to the Middle East — as well as the lack of industrial incentives to develop antivirals for mild infections caused by other, less pathogenic coronaviruses. The continuing threat of MERS-CoV to global health 3 years after its discovery presents a golden opportunity to tackle current obstacles in the development of new anti-coronavirus drugs. A well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, should be formed to carry out clinical trials using anti-coronavirus drugs that have already been shown to be safe and effective in vitro and/or in animal models, particularly lopinavir–ritonavir, interferon beta-1b and monoclonal antibodies and antiviral peptides targeting the viral spike glycoprotein. The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development. The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections. The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.
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