Dual Antiviral and Anti-Inflammatory Properties of 3-epi-betulin Isolated from Daphniphyllum glaucescens Against SARS-CoV-2: A Potential Therapeutic Breakthrough

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SARS-CoV-2, identified as the causative agent of the COVID-19 pandemic, has triggered a global health crisis since its emergence in late 2019. This positive-sense, single-stranded RNA virus has rapidly spread, causing widespread infections and substantial disruptions to public health and the global economy [15].

The virus has undergone genetic variations, leading to the emergence of multiple variants with varying degrees of infectiousness. Understanding the structural and functional aspects of SARS-CoV-2 is crucial for developing effective therapeutic strategies.

Structure and Function of SARS-CoV-2

SARS-CoV-2 consists of structural proteins, including membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S) [16]. Among these, the spike protein plays a pivotal role in inducing inflammation. The receptor-binding domain (RBD) of the spike protein binds to angiotensin converting enzyme 2 (ACE2) on the surface of target cells, facilitating viral entry [17]. Other potential receptors, such as glucose-regulated protein 78 (GRP78) and CD147, have also been proposed [18].

Clinical Manifestations and Inflammatory Response

SARS-CoV-2 is highly contagious, resulting in a spectrum of clinical manifestations ranging from asymptomatic infection to severe respiratory distress. Common symptoms include cough, fever, fatigue, muscle aches, headaches, and shortness of breath. Severe cases can progress to pneumonia and acute respiratory distress syndrome (ARDS) [19]. Inflammation is a key feature of the immune response to the virus, contributing significantly to the symptoms and severity of COVID-19 [20].

The virus induces the release of pro-inflammatory cytokines, including Interleukin-1 beta (IL-1 beta), Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF-alpha), and Interferon-gamma (IFN-gamma), amplifying the inflammatory cascade [21]. Hyper-inflammation is identified as a major driver of severe COVID-19 and the persistence of symptoms in long COVID [22].

Search for Dual Antiviral and Anti-Inflammatory Agents

Given the impact of inflammation on disease severity, there is a critical need for molecules possessing dual antiviral and anti-inflammatory properties. Traditional medicinal plants and their natural product derivatives have a rich history of being used in the prevention and treatment of infectious diseases [23]. Several natural compounds have shown promise as potential candidates for combatting SARS-CoV-2 [24].

Discovery of 3-epi-betulin from Daphniphyllum glaucescens

In a recent study, researchers identified a potential breakthrough in the form of 3-epi-betulin, a compound isolated from Daphniphyllum glaucescens. This natural product demonstrated a dual anti-SARS-CoV-2 effect, exhibiting efficacy in reducing virus-induced inflammation and acting as a broad-spectrum inhibitor for virus entry in a cell culture model.

Discussion: Unraveling the Complexities of SARS-CoV-2 Infection and the Therapeutic Potential of 3-epi-betulin

The clinical spectrum of COVID-19 is extensive, ranging from asymptomatic cases to severe outcomes, underscoring the need for comprehensive therapeutic strategies [20]. Despite the rapid development of vaccines, there is a persistent lack of long-term protective vaccines. Antiviral agents, including protease inhibitors (3CLpro and ritonavir) and polymerase inhibitors (remdesivir and molnupiravir), have demonstrated efficacy in early-stage COVID-19 treatment [21]. However, the imbalanced host-dependent response in COVID-19 patients, characterized by elevated proinflammatory cytokines and chemokines, remains a challenge [22]. Addressing this inflammatory response is crucial for preventing disease progression.

Role of S Protein in SARS-CoV-2-Induced Inflammation:

A growing body of evidence suggests that the spike protein (S) of SARS-CoV-2 is a key player in inducing the inflammatory response [23]. Stimulation with the S protein induces a proinflammatory state in macrophages, characterized by increased TNF-α and MHC-II M1-like phenotype markers. Furthermore, the S protein activates the NF-κB pathway, resulting in the induction of inflammatory cytokines and chemokines [1]. This study’s data supports previous findings, demonstrating that the S protein is integral to SARS-CoV-2-stimulated inflammation.

The role of CD147 as a receptor for SARS-CoV-2 is explored, indicating that its expression on THP-1 cells surpasses ACE2. CD147 knockdown in THP-1 cells resulted in reduced phosphorylated NFκB and proinflammatory cytokine IL-1β levels upon S pseudotyped virus infection, emphasizing the importance of spike attachment to CD147 in SARS-CoV-2-induced inflammation. However, due to ongoing debates on CD147’s roles in SARS-CoV-2 infection, further investigations into the molecular mechanisms underlying spike-induced inflammation are warranted [4,25,26].

Structural Insights into 3-epi-betulin’s Inhibitory Activity:

The study introduces 3-epi-betulin, specifically compound 5, as a potential therapeutic candidate against SARS-CoV-2. Notably, the chemical structure of compound 5 is similar to betulinic acid, which has demonstrated anti-viral activity by inhibiting the spike protein’s binding to ACE2 [18]. Compound 5 exhibited significantly higher inhibitory activity than betulinic acid, attributed to an extra hydrogen bond interaction with residue Y453 and lower binding energy.

Compound 5 demonstrated effectiveness against various SARS-CoV-2 variants, except for the Omicron variant. Structural analysis revealed mutations in G496S, Q498R, and Y505H in the Omicron variant, affecting important binding positions. The study suggests that these mutations may decrease the stability of the spike protein, influencing the binding affinity of compound 5 and explaining its reduced potency against the Omicron strain.

Implications for Future Therapeutics:

The study’s findings propose 3-epi-betulin, specifically compound 5, as a potential adjuvant in current regimens against SARS-CoV-2. The dual functionality of this compound, with both antiviral and anti-inflammatory properties, positions it as a promising candidate for further investigation. Future research and clinical trials will be essential to validate the efficacy and safety of compound 5, bringing us one step closer to a comprehensive therapeutic solution against SARS-CoV-2.

In conclusion, this discussion highlights the multifaceted nature of SARS-CoV-2 infection, emphasizing the importance of targeting the inflammatory response and introducing a novel compound, 3-epi-betulin, as a potential breakthrough in the ongoing battle against COVID-19.


reference link : https://www.mdpi.com/1422-0067/24/23/17040

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