人乳头瘤病毒(HPV)次要衣壳蛋白(L2)的氨基(N)末端区域是高度保守的区域,对于建立病毒感染至关重要。尽管它在病毒感染性中很重要,HPVN末端结构域的作用尚未得到充分表征.使用精细映射分析,我们鉴定了L2N末端的36个氨基酸(aa)的肽序列,称为L2N,这对HPV感染至关重要。在靶细胞表面上具有跨膜序列的L2N的异位表达赋予了对HPV感染的抗性。此外,在羧基(C)末端具有化学或酶促脂化的L2N肽有效地消除靶细胞中的HPV感染。在合成的L2N脂肽中,跨越氨基酸13至46(13-46)的硬脂酰化脂肽表现出最有效的抗HPV活性,半最大抑制浓度(IC50)为200μM。此外,我们证明了13-46st脂肽通过阻断病毒体颗粒的反式高尔基网络逆行运输来抑制HPV进入,导致快速退化。从根本上说,L2N脂肽的抑制作用似乎是进化保守的,因为它们在各种乳头瘤病毒中显示出交叉型抑制。总之,我们的研究结果为L2N序列在HPV进入机制中的关键作用提供了新的见解,并确定了L2N脂肽作为有效的抗HPV药物的治疗潜力.重要性HPV是一种人类致癌病毒,在全球范围内引起重大公共卫生问题,约占人类癌症总数的5%,几乎所有的宫颈癌病例。HPV衣壳由两种结构蛋白组成,主要衣壳L1蛋白和次要衣壳L2蛋白。虽然L2在病毒生命周期中起着关键作用,病毒进入的分子机制仍然难以捉摸。这里,我们对L2N末端区域进行了精细定位,并定义了一个短的36个氨基酸的肽,称为L2N,这对HPV感染至关重要。具体来说,具有羧基末端脂化的L2N肽充当有效的交叉型HPV抑制剂。一起来看,我们研究的数据强调了L2N序列在HPV进入早期阶段的重要作用,并建议L2N脂肽作为广泛预防HPV感染的新策略.
The amino (N)-terminal region of human papillomavirus (HPV) minor capsid protein (L2) is a highly conserved region which is essential for establishing viral infection. Despite its importance in viral infectivity, the role of the HPV N-terminal domain has yet to be fully characterized. Using fine mapping analysis, we identified a 36-amino-acid (aa) peptide sequence of the L2 N terminus, termed L2N, that is critical for HPV infection. Ectopic expression of L2N with the transmembrane sequence on the target cell surface conferred resistance to HPV infection. Additionally, L2N peptide with chemical or enzymatic lipidation at the carboxyl (C) terminus efficiently abrogated HPV infection in target cells. Among the synthetic L2N lipopeptides, a stearoylated lipopeptide spanning aa 13 to 46 (13-46st) exhibited the most potent anti-HPV activity, with a half-maximal inhibitory concentration (IC50) of ∼200 pM. Furthermore, we demonstrated that the 13-46st lipopeptide inhibited HPV entry by blocking trans-Golgi network retrograde trafficking of virion particles, leading to rapid degradation. Fundamentally, the inhibitory effect of L2N lipopeptides appeared to be evolutionarily conserved, as they showed cross-type inhibition among various papillomaviruses. In conclusion, our findings provide new insights into the critical role of the L2N sequence in the HPV entry mechanism and identify the therapeutic potential of L2N lipopeptide as an effective anti-HPV agent.IMPORTANCE HPV is a human oncogenic virus that causes a major public health problem worldwide, which is responsible for approximately 5% of total human cancers and almost all cases of cervical cancers. HPV capsid consists of two structure proteins, the major capsid L1 protein and the minor capsid L2 protein. While L2 plays critical roles during the viral life cycle, the molecular mechanism in viral entry remains elusive. Here, we performed fine mapping of the L2 N-terminal region and defined a short 36-amino-acid peptide, called L2N, which is critical for HPV infection. Specifically, L2N peptide with carboxyl-terminal lipidation acted as a potent and cross-type HPV inhibitor. Taken together, data from our study highlight the essential role of the L2N sequence at the early step of HPV entry and suggests the L2N lipopeptide as a new strategy to broadly prevent HPV infection.