Das Dipon, Smith Nathan W, Wang Xu, Richardson Stacie L, Hartman Matthew C T, Morgan Iain M
VCU Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Department of Oral and Craniofacial Molecular Biology, Richmond, VA 23298, USA.
VCU Department of Chemistry, 1001 W. Main Street, Richmond, VA 23284, USA.
Virology. 2017 Aug;508:180-187. doi: 10.1016/j.virol.2017.04.020. Epub 2017 May 29.
Human papillomaviruses are causative agents in several human diseases ranging from genital warts to ano-genital and oropharyngeal cancers. Currently only symptoms of HPV induced disease are treated; there are no antivirals available that directly target the viral life cycle. Previously, we determined that the cellular protein TopBP1 interacts with the HPV16 replication/transcription factor E2. This E2-TopBP1 interaction is essential for optimal E1-E2 DNA replication and for the viral life cycle. The drug calcein disrupts the interaction of TopBP1 with itself and other host proteins to promote cell death. Here we demonstrate that calcein blocks HPV16 E1-E2 DNA replication via blocking the viral replication complex forming at the origin of replication. This occurs at non-toxic levels of calcein and demonstrates specificity as it does not block the ability of E2 to regulate transcription. We propose that calcein or derivatives could be developed as an anti-HPV therapeutic.
人乳头瘤病毒是多种人类疾病的病原体，范围从生殖器疣到肛门生殖器癌和口咽癌。目前仅对HPV诱导疾病的症状进行治疗；尚无直接针对病毒生命周期的抗病毒药物。此前，我们确定细胞蛋白TopBP1与HPV16复制/转录因子E2相互作用。这种E2-TopBP1相互作用对于最佳的E1-E2 DNA复制和病毒生命周期至关重要。药物钙黄绿素会破坏TopBP1与其自身及其他宿主蛋白的相互作用，从而促进细胞死亡。在此我们证明，钙黄绿素通过阻断在复制起点形成的病毒复制复合体来阻断HPV16 E1-E2 DNA复制。这在钙黄绿素的无毒水平下发生，并显示出特异性，因为它不会阻断E2调节转录的能力。我们提出，钙黄绿素或其衍生物可开发成为一种抗HPV治疗药物。
