Multi-Pronged Approach for the Discovery of Novel Antivirals Against HIV

Joint research project

Project leaders: Enzo Tramontano, Liang-tzung Lin
Agreement: TAIWAN - NSTC - National Science and Technology Council
Call: CNR/MoST biennio 2018-2019 2018-2019
Department: Biology, agriculture and food sciences
Thematic area: Biology, agriculture and food sciences
Status of the project: New

Research proposal

Abstract
At present, the acquired immune deficiency syndrome (AIDS)-inducing human immunodeficiency virus (HIV) remains a significant medical burden worldwide. In Taiwan, an increase rate of infections has been observed especially in the younger age individuals, which account for up to 30% of the total newly infected population at the ended of 2014 [1]. Despite the use of the highly active antiretroviral therapy (HAART), drug resistance issues and the lack of a cure and preventive vaccine will likely project further morbidity/morality associated with HIV infections in the near future. These issues highlight the importance of developing additional antivirals that could help in the management of HIV cases. Furthermore, several studies have suggested that natural products are a potential source of antiretroviral drug discovery and set precedent for assessing such small molecules as candidate agents. In this proposal, the two laboratories (Dr. Liang-Tzung Lin in Taipei Medical University, Taiwan and Dr. Enzo Tramontano in the CNR in Cagliari, Italy) join their expertise to employ a multi-pronged approach to dissect the viral life cycle (pre-entry, viral entry, and post-entry) and identify novel anti-HIV drug candidates from plant-based natural products using reporter-based HIV pseudoparticle system (for analysis of viral entry) and viral replicase assays (for analysis of viral replication). In addition, the identified candidates will be evaluated against other viral infections to address co-infection scenarios. Finally, molecular docking analysis is employed to identify the mechanistic target of the candidate agents. The above approach allows a mechanistic discovery of novel inhibitors and the use of the reporter system also permits a high-throughput analysis. The obtained results will help expand the scope of candidate antivirals for prophylactic and/or therapeutic application to better manage the global HIV epidemic and reduce the social and medical burden of AIDS. As the natural products are plant-based, results from this study have implications in stimulating agricultural industry for biopharma development of antivirals.
A. Background
HIV is responsible for causing significant global morbidities and mortalities, with an about 2-3 million new infections occurring annually [2]. In 2013, it has been estimated that around 700 children were infected every day globally, resulting in more than 240,000 children reported positive with HIV in that year [3]. In Taiwan, the number of HIV infections has been increasing, amounting to about 30,000 cases, and in 2014, 658 cases or 29.4% of the total newly infected individuals have been reported to occur under 24 years of age [1]. This reflects that while there is an increase in HIV-infected population in the country, most importantly the age of the infected individual is decreasing, which poses significant concern for public health in Taiwan.
HIV contains two copies of the viral positive-sense ssRNA genome at its core, and is surrounded by host-derived lipid membrane inserted with the Env gene-encoded glycoproteins (gp160, processed to yield the surface gp120 and the transmembrane gp41) [4]. The glycoproteins mediate the entry steps of HIV into the targeted host cells whereas the viral enzymatic activities (reverse transcriptase [RT], RNase H, integrase [IN], and HIV protease) encoded by the Pol gene are crucial to viral replication [4].
Impact on Society and Global Health
The joint collaborative effort made possible with this MOST-CNR project is expected to help establish the multi-pronged platform for discovering novel antivirals against HIV. In addition, it is anticipated that various candidates will be identified for further clinical development. Results from this study have important social impact on the society and global health, as it promotes safeguarding of public health and aid the prevention/management of local and worldwide HIV epidemics. In addition, results from this study can also help stimulate local biopharmaceutical, agricultural, and economic interests, and promote local pharmaceutical industries and Taiwan as world-class developers of HIV antivirals.
Potential Contributions to Academics, National Developments, or Other Applications
o These studies help develop novel antiviral therapeutics against HIV infection and provide insights for potential prophylactic and therapeutic application in clinical setting.
o The multi-pronged platform can be further tailored in the future for the discovery of novel antivirals against other emerging/re-emerging viruses (e.g. dengue, ebola, influenza, zika, etc.).
o These studies will also promote Taiwan and Italy as competitive developers of antivirals in the international arena and could stimulate interests of both local/foreign pharmaceutical industries.
o Since the natural products are plant-based, this could stimulate local agricultural industry for biopharma development of antivirals.
Expected Research Results and Achievements
Results will be submitted to high impact and top ranking journals such as Antiviral Research, Journal of Virology, Journal of Infectious Diseases, and PLOS Pathogens. Potential patents will be applied and data will be presented at relevant domestic and international conferences and symposiums to increase exposure of this study to the scientific community. These endeavours will help attract international recognition and interest in this Taiwan-Italy joint research development of antiviral therapy against HIV and reinforce international collaborations to advance medical development.
Potential Training to be Gained by Personnel Participating in this Project
These studies will help the professional formation of the participating researchers from both Taiwan and Italy in building advanced research skills, gaining international research experience, and networking for global partnerships.

Research goals

The objective is to use a multi-pronged approach to identify key antiviral candidates from a list of natural products and their derivatives against HIV infection. we will use a reporter-based HIV pseudovirus system, which consists of replication defective HIV-like virion bearing HIV glycoproteins, in combination with viral entry-specific assays and HIV polymerase activities analysis to screen a panel of plant-derived natural products, such as the tannin, triterpene, flavonoid, and quinone classes of compounds. This method allows a mechanistic approach in identifying candidate antiviral agents blocking a specific step in the viral life cycle. In addition, the identified agents will be further evaluated by molecular docking analysis to confirm their target of inhibition, and also evaluated for antiviral effect against HCV infection to potentially address HIV-HCV co-infection scenario. Results will yield potential antiviral candidates against the different steps of the HIV life cycle that could be further developed for prophylactic and/or therapeutic application to improve the management of the HIV/AIDS epidemic. In addition, since the small molecules are extracted from plants that are cultivable in Taiwan, such as gallic acid from Limonium sinense, berberine from Rhizoma coptidis, and saikosaponins from Bupleurum kaoi, identification of the potential antiretroviral small molecules can promote the agriculture industry for the plantation of such medicinal plants for therapeutics.

Last update: 08/06/2025