Enantioselective Inhibition of Human Papillomavirus L1 Pentamer Formation by Chiral‐Proline Modified Calix[4]arenes: Targeting the Protein Interface
Enantioselective Inhibition of Human Papillomavirus L1 Pentamer Formation by Chiral‐Proline Modified Calix[4]arenes: Targeting the Protein Interface
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DOI：
10.1002/slct.201601467
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Dingyi Fu;Tong Lu;Yu-Xue Liu;Fei Li;M. Ogden;Ye Wang;Yuqing Wu;M. Mocerino
中科院分区：
文献类型：
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作者：
Dingyi Fu;Tong Lu;Yu-Xue Liu;Fei Li;M. Ogden;Ye Wang;Yuqing Wu;M. Mocerino
虽然目前的人乳头瘤病毒（HPV）疫苗可以很好地防止感染，但它们仅对有限数量的亚型有效。再加上目前临床上没有有效的处方可用于治疗的困境，迫切需要开发新的抗HPV药物。在本研究中，研究了l-和d-脯氨酸修饰的杯[4]芳烃（Pro-C4 A），以确定它们对HPV 16 L1五聚体（L1-p）组装的影响的任何差异。利用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF-MS）和核磁共振（NMR）研究了模型肽的作用机制，发现结合靶向L1界面的碱性残基。这也得到了胰蛋白酶消化实验和对全长L1进行的分子模拟的充分支持。通过分子模拟揭示的大的能量和形态差异解释了l-和d-Pro-C4 A与L1的结合差异，并因此解释了它们对L1-p形成的选择性抑制。本研究为开发具有对映体选择性和成本效益的L1-p形成抑制剂开辟了一条道路，这可能被用作一种新型的抗HPV药物，并可扩展到基于类似机制的其他病毒。
Although current human papillomavirus (HPV) vaccines can protect well against infection, they are effective only for a limited number of subtypes. Coupled with the dilemma that no efficient prescription is currently clinically available for therapy, there is an urgent need to develop new anti-HPV agents. In the present study l- and d-Proline modified calix[4]arenes (Pro-C4 A) were investigated to determine any differences in their effect on the assembly of HPV 16 L1 pentamer (L1-p). The mechanism of action using model peptides was investigated by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) and Nuclear Magnetic Resonance (NMR) and revealed that the binding was targeting the basic residues at L1 interface. This was also well supported by the trypsin digestion experiments and molecular simulations performed on the full-length L1. The large energy and morphology differences revealed by molecular simulations explain the binding disparity of l- and d-Pro-C4 A to L1, and consequently the selective inhibition of them on L1-p formation. The present study opens a way to develop enantioselective and cost-effective inhibitors for L1-p formation, which might be used as a new kind of anti-HPV agent and could be extended to other viruses based on similar mechanisms.