Specific inhibition of the interaction between pseudorabies virus DNA polymerase subunits UL30 and UL42 by a synthetic peptide
Specific inhibition of the interaction between pseudorabies virus DNA polymerase subunits UL30 and UL42 by a synthetic peptide
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合成肽对伪狂犬病病毒 DNA 聚合酶亚基 UL30 和 UL42 之间相互作用的特异性抑制
DOI：
10.1016/j.vetmic.2022.109517
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发表时间：
2022
影响因子：
3.3
通讯作者：
Liping Huang
中科院分区：
文献类型：
--
作者：
Yiping Wang;Yanwu Wei;Hongli Wu;Li Feng;Liping Huang
伪狂犬病病毒（Pseudorabies virus，PRV）是一种广泛存在的、具有重要经济意义的猪α疱疹病毒，在世界范围内引起严重的猪病。PRV编码的DNA依赖性DNA聚合酶由催化亚基UL 30和辅助亚基UL 42组成，是病毒复制所必需的。PRV UL 30和UL 42作为异源二聚体，其中UL 30具有固有的DNA聚合酶活性，UL 42赋予DNA聚合酶全酶的持续合成能力。通过蛋白质-蛋白质相互作用形成PRV UL 30/UL 42异二聚体全酶对于病毒复制是必不可少的。在本文描述的工作中，我们确定了介导PRV UL 30/UL 42相互作用的关键结构域，并发现PRV UL 30的41个羧基末端氨基酸区域对于其与UL 42的相互作用至关重要。有趣的是，对应于这41个羧基末端氨基酸残基的合成肽通过竞争性结合UL 42有效地破坏PRV UL 30/UL 42相互作用。这些发现表明，来自PRV DNA聚合酶UL 30/UL 42亚基界面的肽可能是设计针对PRV感染的新型干预策略的潜在靶点。这项工作进一步加强的概念，疱疹病毒DNA聚合酶催化亚基利用其极端的羧基末端结构域作为一个保守的机制，与他们的同源辅助亚基，为我们提供了机会，设计新的抗疱疹病毒感染的抗病毒药物，通过破坏疱疹病毒DNA聚合酶亚基的相互作用。
Pseudorabies virus (PRV) is a ubiquitous and economically important swine alphaherpesvirus that causes devastating swine diseases worldwide. PRV-encoded DNA-dependent DNA polymerase, comprised of the catalytic subunit UL30 and the accessory subunit UL42, is essential for viral replication. PRV UL30 and UL42 act as a heterodimer with UL30 harboring inherent DNA polymerase activity and UL42 conferring processivity on the DNA polymerase holoenzyme. The formation of PRV UL30/UL42 heterodimer holoenzyme through protein-protein interactions is indispensable for viral replication. In work described here, we defined the key domains that mediate PRV UL30/UL42 interaction, and found that the 41 carboxy-terminal amino acids region of PRV UL30 is critical for its interaction with UL42. Intriguingly, a synthetic peptide corresponding to these 41 carboxy-terminal amino acid residues efficiently disrupted PRV UL30/UL42 interaction through competitively binding to UL42. These findings suggest that the peptides from the PRV DNA polymerase UL30/UL42 subunit interface may represent potential targets for designing a novel intervention strategy against PRV infection. This work further strengthens the concept that the herpesvirus DNA polymerase catalytic subunits utilize their extreme carboxy-terminal domains as a conserved mechanism to associate with their cognate accessory subunits, providing us the opportunity of designing novel antiviral agents against herpesvirus infection through disruption of the herpesvirus DNA polymerase subunit interactions.