Pressurized DNA state inside herpes capsids-A novel antiviral target
Pressurized DNA state inside herpes capsids-A novel antiviral target
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DOI：
10.1371/journal.ppat.1008604
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发表时间：
2020-07-01
期刊：
影响因子：
6.7
通讯作者：
Evilevitch, Alex
中科院分区：
文献类型：
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作者：
Brandariz-Nunez, Alberto;Robinson, Scott J.;Evilevitch, Alex
病毒的耐药性是医疗保健的主要挑战之一。作为提供避免耐药性可能性的治疗方法的一部分，我们发现了一种新的作用机制（MOA）和特定的化合物来治疗所有9种人类疱疹病毒和动物疱疹病毒。新型MOA靶向病毒衣壳中的加压基因组状态，“关闭”衣壳压力，并阻断病毒基因组喷射到细胞核中，防止病毒复制。这项工作作为一个概念验证，以证明一种新的抗病毒靶点的可行性-抑制压力驱动的病毒基因组喷射-这可能是不受耐药性的发展。这一关键发现为发现疱疹病毒和其他具有基因组压力依赖性复制的病毒感染的新型广谱治疗提供了平台。抗病毒治疗的生物物理方法也是防止新出现病毒传播的重要策略，其中疫苗开发受到高突变率或其他逃避机制的挑战。基于新的作用机制的疱疹治疗，所述新的作用机制通过扰乱病毒内的病毒基因组压力来干扰疱疹基因组喷射到宿主细胞中，蛋白质外壳，称为衣壳。这种干扰阻止了病毒感染。靶向疱疹衣壳内的加压DNA状态提供了一个平台，用于开发针对所有人类和动物疱疹病毒的广谱治疗，这些病毒不易于基于突变的耐药性发展。
Drug resistance in viruses represents one of the major challenges of healthcare. As part of an effort to provide a treatment that avoids the possibility of drug resistance, we discovered a novel mechanism of action (MOA) and specific compounds to treat all nine human herpesviruses and animal herpesviruses. The novel MOA targets the pressurized genome state in a viral capsid, "turns off" capsid pressure, and blocks viral genome ejection into a cell nucleus, preventing viral replication. This work serves as a proof-of-concept to demonstrate the feasibility of a new antiviral target-suppressing pressure-driven viral genome ejection-that is likely impervious to developing drug resistance. This pivotal finding presents a platform for discovery of a new class of broad-spectrum treatments for herpesviruses and other viral infections with genome-pressure-dependent replication. A biophysical approach to antiviral treatment such as this is also a vital strategy to prevent the spread of emerging viruses where vaccine development is challenged by high mutation rates or other evasion mechanisms.Author summary This work presents a proof-of-concept for anti-herpes treatment based on a novel mechanism of action that interferes with ejection of herpes genome into a host cell by perturbing the viral genome pressure inside the virus' protein shell, termed a capsid. This interference stops viral infection. Targeting the pressurized DNA state inside a herpes capsid presents a platform for development of broad-spectrum treatments for all human-and animal herpesviruses that are not susceptible to mutation-based resistance development.