In May 2023, the World Health Organization (WHO) declared the end of the COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2, marking a significant milestone in the global battle against the virus. However, it is essential to understand that the declaration does not signify the complete elimination of the virus or the absence of potential risks associated with it [1]. While countries have gradually returned to normalcy and vaccination rates have seen fluctuations, there remains a constant threat of new viral mutants and a potential resurgence of the disease.
Despite progress in vaccination efforts, certain segments of the population, particularly the elderly and individuals with comorbid conditions, remain vulnerable to severe illness and strain on healthcare systems [2]. To address this ongoing challenge, the development of effective pharmacotherapies to reduce disease severity and hospitalizations remains a critical endeavor.
The research community has identified several key proteins and processes as potential targets for antiviral medications to combat COVID-19. These include helicases, transmembrane serine protease 2, cathepsin L, cyclin G-associated kinase, adaptor-associated kinase 1, two-pore channel, viral virulence factors, 3-chymotrypsin-like protease (3CLpro), papain-like protease, RNA-dependent RNA polymerase (RdRp), excessive inflammatory responses, endocytosis, and various viral membrane and nucleocapsid proteins [3].
Among these potential targets, only two have been successfully utilized in drug design so far: RdRp and 3CLpro [3]. The 3CLpro enzyme plays a pivotal role in generating nonstructural proteins crucial for viral replication, making it a prime candidate for drug development [7,8].
Research has unveiled a key mechanism for inhibiting 3CLpro, which involves binding to specific amino acid residues within the enzyme’s flexible loop region, particularly Gly143, Ser144, and Cys145 [9]. This binding stabilizes the transition state’s negative charge, reducing the activation energy required for the reaction and promoting catalysis [10]. The enzyme’s catalytic center comprises S1′ and S2′ pockets, which interact with various amino acid residues [9,11,12].
Two drugs that have received approval for COVID-19 pharmacotherapy target 3CLpro. The first is nirmatrelvir, included in Pfizer’s Paxlovid®, which was FDA-approved in 2023 for managing mild-to-moderate COVID-19 in high-risk adults [13]. The second is ensitrelvir, developed by Hokkaido University and Shionogi & Co., Ltd., and granted emergency regulatory approval in Japan for clinical use [14]. Both drugs have demonstrated promising antiviral effects in vitro and in vivo [15], emphasizing the significance of continued research into 3CLpro inhibitors for SARS-CoV-2 [16].
One emerging avenue of research in medicinal chemistry involves harnessing natural compounds as a starting point for antiviral agents [17,18,19,20]. Researchers have identified effective inhibitors derived from compounds such as borneol, triterpene acids, and glycyrrhizic acid nicotinates [21,22,23]. Among these, usnic acid has shown activity against various coronavirus strains [24]. Recent investigations into thiazohydrazones based on (+)- and (−)-usnic acid and p-methoxybenzylidene derivatives have displayed potent activity against the main viral protease [25]. Notably, furan-containing derivatives exhibited the highest efficacy against both proteases and infectious viruses.
TABLE 1 – Usnic Acid
- Origin and Occurrence: Usnic acid is a yellow pigment found in various lichens, primarily belonging to the genera Usnea and Ramalina. These lichens grow on trees, rocks, and soil worldwide.
- Chemical Structure and Properties: Usnic acid is a dibenzofuran derivative with a diverse range of biological activities, including antibacterial, antifungal, anti-inflammatory, and antioxidant properties.
- Safety and Toxicity: Although generally considered safe in topical applications, oral ingestion of usnic acid can cause liver damage and other adverse effects. Further research is needed to determine safe clinical dosages and administration methods.
Antiviral Activity of Usnic Acid against Coronaviruses
- Early Studies: Research into usnic acid’s antiviral activity dates back decades, including studies demonstrating efficacy against several viruses, including herpes simplex virus, influenza virus, and human immunodeficiency virus (HIV).
- SARS-CoV-2 Inhibition: Recent studies have specifically explored the potential of usnic acid against SARS-CoV-2. In vitro and in silico (computer-based) studies have shown promising results, indicating usnic acid’s ability to inhibit the virus’s replication at various stages.
- Mechanism of Action: The exact mechanism of usnic acid’s antiviral activity against coronaviruses is still under investigation. However, proposed mechanisms include:
- Targeting the main protease: Usnic acid might bind to the main protease of the virus, an enzyme crucial for viral replication.
- Disrupting the viral envelope: Usnic acid may interfere with the structure and integrity of the viral envelope, hindering its ability to enter host cells.
- Modulating the immune response: Usnic acid could potentially stimulate the immune system’s response to the virus.
Key Research Findings and Considerations
- Comparative Efficacy: Studies comparing usnic acid with established antiviral drugs, such as remdesivir, have shown similar or even superior efficacy against SARS-CoV-2 in vitro.
- Derivatives and Analogs: Research is ongoing on developing synthetic derivatives and analogs of usnic acid with improved antiviral activity and optimized properties for pharmaceutical development.
- Challenges and Limitations: While promising, usnic acid faces several challenges before clinical use:
- Limited bioavailability: Current formulations of usnic acid demonstrate poor absorption and distribution in the body.
- Potential toxicity: Further research is needed to establish safe dosages and potential side effects in humans.
- Clinical trials: Rigorous clinical trials are crucial to evaluate the efficacy and safety of usnic acid in treating COVID-19 patients.
However, it is crucial to address potential stability issues of furan derivatives in storage and biological environments. To explore new options, researchers have turned their attention to thiophene compounds, known for their diverse biological activities, including anticancer, antimicrobial, anti-inflammatory, antidepressant, analgesic, and anticonvulsant properties [26,27,28,29,30,31]. Substituted and condensed thiophenes are believed to be less toxic [32], making them an attractive candidate for antiviral research.
Studies have demonstrated the effectiveness of thiophene-containing compounds against various viruses, including influenza and Zika [33,34,35]. In this study, researchers synthesized derivatives of (+)- and (−)-usnic acid containing unsubstituted thiophenes or methyl-, bromo-, or nitrothiophenes. These derivatives were subjected to in silico and in vitro testing to evaluate their potential activity against the main viral protease of SARS-CoV-2, opening up new possibilities in the quest for effective antiviral agents.
In conclusion, while the end of the COVID-19 pandemic has been declared, the threat of the virus and its variants persists. Ongoing research into antiviral compounds targeting critical viral proteins like 3CLpro is essential to combat the disease effectively. The use of natural compounds and the exploration of thiophene derivatives offer promising avenues to expand the arsenal of tools in the fight against COVID-19. This multidisciplinary approach exemplifies the global scientific community’s dedication to finding innovative solutions to address the ongoing challenges posed by the virus.
https://www.mdpi.com/1999-4915/16/2/215
