COVID-19 News: Phytochemical Alisol B 23-Acetate Broadly Blocks Coronavirus Entry And Suppresses Proinflammatory T Cells Responses In COVID-19!

COVID-19 News: The COVID-19 pandemic has brought the world to its knees, necessitating a global quest for effective treatments. As the virus responsible for COVID-19, SARS-CoV-2 continues to mutate and pose challenges for public health, finding novel therapeutic agents has become an urgent priority. Researchers from the University of Hong Kong-China, Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park-China, and The University of Hong Kong-Shenzhen Hospital, Shenzhen-China, have made a remarkable breakthrough in the battle against the virus. Their study introduces Alisol B 23-Acetate (AB23A), a natural triterpenoid compound found in the rhizomes of Alisma orientalis, as a potent candidate for COVID-19 treatment. This compound not only inhibits coronavirus entry but also suppresses proinflammatory T-cell responses. In this COVID-19 News report, we delve into the details of this groundbreaking research.


 
The Ongoing Challenge of COVID-19
Since the emergence of SARS-CoV-2 in 2019, the world has grappled with three major coronavirus outbreaks, including Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. Among these, COVID-19 has proven to be the most devastating, spreading rapidly and causing substantial health and economic devastation. The virus primarily enters human cells by binding its spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor. Over time, various variants of SARS-CoV-2 have emerged, including Alpha, Delta, and the highly transmissible Omicron variants. These variants present unique challenges, including increased antibody evasion and potential resistance to existing treatments.
 
Challenges in COVID-19 Treatment
Efforts to develop effective COVID-19 treatments have faced numerous challenges. Initially, drugs like remdesivir, hydroxychloroquine, and lopinavir-ritonavir were repurposed for COVID-19 treatment but yielded mixed and often unsatisfactory results. The use of interleukin-6 receptor inhibitors like tocilizumab and sarilumab showed promise in improving survival rates in severe COVID-19 cases. Paxlovid, a protease inhibitor targeting the main protease of SARS-CoV-2, exhibited antiviral activity but raised concerns about viral rebound in Omicron variant infections. The rapid mutation rate of SARS-CoV-2, especially in the Omicron variant, underscores the need for new therapeutic agents that can effectively combat the virus and its future variants.
 
The Potential of Natural Medicinal Compounds
Traditional Chinese Medicine (TCM) has a rich history of combating epidemic infectious diseases. Several TCM formulations have been recommended for COVID-19 treatment in China, with promising results. One such formulation is QingFei PaiDu (QFPD) Decoction, which has been evaluated for its safety and effectiveness as an adjunct therapy alongside conventional treatments. QFPD contains various compounds with antiviral, anti-inflammatory, and immunomodulatory properties, such as Oroxylin A, hesperetin, scutellarin, glycyrrhizic acid, and glycyrrhizin. Among these compounds, researchers selected 35 active candidates for screening based on existing literature.
 
The Discovery of Alisol B 23-Acetate (AB23A)
In the screening process, one compound stood out: Alisol B 23-Acetate (AB23A). This active compound is naturally found in Alisma orientalis and is part of the triterpenoid family. Prior research had shown that Alisol B 23-Acetate had antibacterial, anti-inflammatory, and hepatoprotective properties. These qualities sparked interest in exploring its potential against SARS-CoV-2 and its variants.
 
Alisol B 23-Acetate's Broad Spectrum Antiviral Properties
The research team conducted a series of experiments to evaluate AB23A's antiviral properties. They found that AB23A exhibited inhibitory effects on various coronavirus species, including MERS-CoV, SARS-CoV-2, Alpha variant, Delta variant, and the Omicron variant and its sub-lineage BA.5.2. This broad-spectrum activity suggested AB23A's potential as a pan-coronavirus inhibitor.
 
How AB23A Inhibits Viral Entry
To understand how AB23A inhibits viral entry, researchers used pseudotyped Vesicular Stomatitis Virus (VSV) and cells overexpressing ACE2 receptors. Their experiments revealed that AB23A effectively blocked the entry of SARS-CoV-2 and its variants into host cells. These findings suggested that AB23A interferes with the binding of the virus's spike protein to ACE2 receptors on host cells.
 
The Molecular Mechanism: Hydrogen/Deuterium Exchange (HDX) Mass Spectrometry
To gain insight into the molecular interactions between AB23A and ACE2, researchers turned to hydrogen/deuterium exchange (HDX) mass spectrometry. This technique allowed them to identify potential binding sites of AB23A on ACE2. The results indicated that AB23A interacted with specific regions of ACE2, including residues crucial for the ACE2-Spike protein interaction. This interaction was believed to be one of the mechanisms by which AB23A inhibits viral entry.
 
In Vivo Efficacy of AB23A
The promising in vitro results prompted researchers to test AB23A's efficacy in animal models. They used hamsters and human ACE2 transgenic mice infected with SARS-CoV-2 and its variants. Treatment with AB23A significantly reduced viral copy numbers, mitigated lung damage, and suppressed the infiltration of proinflammatory immune cells in hamsters. In human ACE2 transgenic mice infected with the Omicron variant, AB23A effectively reduced viral load in nasal turbinate and lowered levels of proinflammatory cytokines, specifically interleukin 17 (IL17) and interferon γ (IFNγ). Additionally, prophylactic intranasal administration of AB23A reduced viral load in hamster lung tissues.
 
AB23A's Anti-Inflammatory Properties
COVID-19 is often accompanied by a cytokine storm, where excessive inflammation contributes to severe lung injury and other complications. AB23A's potential to mitigate inflammation was examined both in vivo and in vitro. It was found to reduce superoxide and peroxynitrite levels, both critical mediators of lung damage in COVID-19. Moreover, AB23A reduced the levels of proinflammatory cytokines such as IL17, IFNγ, and TNFα in the serum of infected animals. It also inhibited the infiltration of T cells and macrophages in lung tissues. In vitro experiments further demonstrated AB23A's ability to suppress the secretion of IL17 and IFNγ in lymphocytes.
 
Safety and Future Research
While AB23A showed potential cytotoxicity in vitro, it was deemed safe in acute toxicity studies in hamsters, even at doses six times higher than the therapeutic dosage used in the study. The compound's pharmacokinetics, pharmacodynamics, and long-term safety require further investigation. Additionally, researchers envision developing AB23A into various formulations, including nasal sprays and sustained-release preparations, to optimize its translational application.
 
Conclusion
In summary, the discovery of Alisol B 23-Acetate (AB23A) represents a significant breakthrough in the quest for effective COVID-19 treatments. This natural triterpenoid compound exhibited broad-spectrum antiviral properties by inhibiting coronavirus entry and demonstrated potent anti-inflammatory effects. The mechanisms of action included interference with the ACE2-Spike protein interaction and suppression of proinflammatory immune responses. AB23A's safety profile in acute toxicity studies suggests its potential as a promising therapeutic agent for COVID-19 treatment. Moreover, the versatility of AB23A as a potential prophylactic and therapeutic agent against various coronavirus variants adds to its significance in the ongoing battle against the pandemic and future emerging coronaviruses. Further research is essential to explore its full potential and bring it closer to clinical application.
 
The study findings were published in the peer reviewed Journal of Advanced Research.
https://www.sciencedirect.com/science/article/pii/S2090123223002941
 
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