Title:Discovery of Ten Anti-HIV Hit Compounds and Preliminary
Pharmacological Mechanisms Studies
Volume: 22
Issue: 2
Author(s): Yushan Lian, Zhimin Huang, Xinyi Liu, Zhicheng Deng, Dan Gao*Xiaohui Wang*
Affiliation:
- The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical
Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
- Department of Prevention and control of infectious diseases, School of public health, Southern Medical University,
Guangzhou, Guangdong, China
- Department of HIV/AIDS Prevention and Control, Shenzhen Center for Disease
Control and Prevention, Shenzhen, Guangdong, China
Keywords:
Bruceine D, HIV, drug screening, precursor compounds, harringtonine, natural product molecular libraries, antiviral molecular libraries.
Abstract:
Background: The research and development of HIV drugs is very important, but at the
same time it is a long cycle and expensive system project. High-throughput drug screening systems
and molecular libraries of potential hit compounds remain the main ways for the discovery
of hit compounds with anti-HIV activity.
Objective: The aim of this study was to screen out the hit compounds against HIV-1 in the natural
product molecule library and the antiviral molecule library, and elucidate the molecular mechanism
of their inhibition of HIV-1, so as to provide a new choice for AIDS drug research.
Methods: In this study, a drug screening system using HIV Rev-dependent indicator cell line
(Rev-A3R5-GFP reporter cells) with pseudoviruses (pNL4-3) was used. The natural drug
molecule library and antiviral molecule library were screened, and preliminary drug mechanism
studies were performed.
Results: Ten promising hit compounds were screened. These ten molecules and their drug inhibitory
IC50 were as follows: Cephaeline (0.50 μM), Yadanziolide A (8.82 μM), Bruceine D (2.48
μM), Astragaloside IV (4.30 μM), RX-3117 (1.32 μM), Harringtonine (0.63 μM), Tubercidin
(0.41 μM), Theaflavine-3, 3'-digallate (0.41 μM), Ginkgetin (10.76 μM), ZK756326 (5.97 μM).
The results of the Time of additions showed that except for Astragaloside IV and Theaflavine-3,
3'-digallate had a weak entry inhibition effect, and it was speculated that all ten compounds had
an intracellular inhibition effect. Cephaeline, Harringtonine, Astragaloside IV, Bruceine D, and
Tubercidin may have pre-reverse transcriptional inhibition. Yadanziolide A, Theaflavine-3, 3'-digallate,
Ginkgetin and RX-3117 may be in the post-reverse transcriptional inhibition. The inhibitory
effect of ZK 75632 may be in the reverse transcriptional process.
Conclusion: A drug screening system using Rev-A3R5-GFP reporter cells with pseudoviruses
(pNL4-3) is highly efficient. This study provided potential hit compounds for new HIV drug
research.
