Inhibition of Human Immunodeficiency Virus Type 1 Entry by a Keggin Polyoxometalate

Wang, Xiaoli; Wang, Jiao; Zhang, Wenmei; Li, Boye; Zhu, Ying; Hu, Qin; Yang, Yishu; Zhang, Xiaoguang; Yan, Hong; Zeng, Yi

The current antiretroviral therapy is a combination of three or more antiretroviral drugs that target different steps of HIV-1 life cycle. Despite the fact that it reduces the viral load to an undetectable level and has greatly improved survival rates and life quality of HIV-infected patients, it still faces challenges including long-term drug resistance, unwanted drug-drug interactions and low compliance of patients. Thus, the discovery of multifunctional agents that interact simultaneously with more than one target has proven effective in anti-HIV leads discovery. For instance, inducible T cell kinase (ITK) and mammalian target of rapamycin (mTOR) inhibitors blocked multi-steps of HIV replication, including viral entry, reverse transcription, integration, and viral particle production [45, 46] . Many plant-derived polyphenols such as quercetin, isoflavones, flavanones and phenolic acid derivatives, showed activity against various viral enzyme targets simultaneously [47] . Importantly, HIV protease inhibitors were found not only affecting virion release, but also blocking viral entry, reverse transcription and post-reverse transcription [48] . In the present study, we have identified the multi-target profile of PT-1, which not only blocked viral entry, but also interfered with main HIV enzymes reverse transcriptase and integrase In addition, POMs could be easily modified by various chemical reactions to enhance the specificity or activity, and they are less expensive than organic agents. We synthesized a serial of POMs derivatives by decorating PT-1 with amino acid to improve biocompatibility, and the modifications did not affect anti-viral activity. Thus, PT-1 has shown some promising properties for drug development. It is also important to note that the pharmacokinetic and pharmacodynamics profile of most metal-based compounds have yet to be identified and warrant further investigation.