Savva Renos
Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
Microorganisms. 2020 Mar 24;8(3):461. doi: 10.3390/microorganisms8030461.
Vast evolutionary distances separate the known herpesviruses, adapted to colonise specialised cells in predominantly vertebrate hosts. Nevertheless, the distinct herpesvirus families share recognisably related genomic attributes. The taxonomic Family includes many important human and animal pathogens. Successful antiviral drugs targeting are available, but the need for reduced toxicity and improved efficacy in critical healthcare interventions invites novel solutions: immunocompromised patients presenting particular challenges. A conserved enzyme required for viral fitness is Ung, a uracil-DNA glycosylase, which is encoded ubiquitously in genomes and also host cells. Research investigating Ung in dynamics has uncovered an unexpected combination of viral co-option of host Ung, along with remarkable Subfamily-specific exaptation of the virus-encoded Ung. These enzymes apparently play essential roles, both in the maintenance of viral latency and during initiation of lytic replication. The ubiquitously conserved Ung active site has previously been explored as a therapeutic target. However, exquisite selectivity and better drug-like characteristics might instead be obtained via targeting structural variations within another motif of catalytic importance in Ung. The motif structure is unique within each Subfamily and essential for viral survival. This unique signature in highly conserved Ung constitutes an attractive exploratory target for the development of novel beneficial therapeutics.
已知的疱疹病毒在进化上相距甚远，它们适应于在主要是脊椎动物宿主的特定细胞中定殖。然而，不同的疱疹病毒科具有明显相关的基因组特征。疱疹病毒科包含许多重要的人类和动物病原体。目前已有针对疱疹病毒的成功抗病毒药物，但在关键的医疗干预中，降低毒性和提高疗效的需求促使人们寻求新的解决方案：免疫功能低下的患者面临着特殊的挑战。一种病毒适应性所必需的保守酶是Ung，一种尿嘧啶-DNA糖基化酶，它在疱疹病毒基因组以及宿主细胞中普遍编码。对疱疹病毒中Ung动态变化的研究发现了宿主Ung被病毒利用以及病毒编码的Ung在亚科特异性方面的显著适应的意外组合。这些酶显然在维持病毒潜伏以及裂解复制起始过程中都起着至关重要的作用。Ung中普遍保守的活性位点此前已被探索作为治疗靶点。然而，通过靶向Ung中另一个具有催化重要性的基序内的结构变异，可能会获得更高的选择性和更好的类药物特性。该基序结构在每个亚科中都是独特的，并且对病毒存活至关重要。高度保守的Ung中的这种独特特征构成了开发新型有益疗法的一个有吸引力的探索靶点。
