(Influenza) Potential natural antivirals against IAV
Plant extracts as a source of antiviral agents against influenza A virus.
Journal of Applied Microbiology, Vol 136, Issue 3.
The influenza virus, commonly known as the ‘common cold’, is the etiological agent of multiple respiratory pandemics and seasonal endemics. Affecting approximately 5 million individuals annually, accompanied by 650 000 deaths, especially among elderly individuals (aged ≥65 years), there is a need to address the demand for effective antiviral and vaccines (World Health Organization [WHO] 2024). Influenza viruses (Orthomyxoviridae family) are RNA viruses that can be classified into four different types, namely A, B, C, and D, with the former two, influenza A virus (IAV) and influenza B virus (IBV), possessing a greater relevancy to human respiratory infection. Of these, IAV has contributed to major human pandemics over the past few decades (van Doorn and Yu 2020, Low et al. 2023) and, thus, is the focus of this review.
Accounting for four pandemics—the 1918 Spanish Flu pandemic, the 1957 Asian flu pandemic, the 1968 Hong Kong flu pandemic, and the 2009 Swine flu pandemic, the IAV is the most documented and monitored influenza virus. These were all brought by novel IAV subtypes that have capacities for rapid circulation among the global population (Saunders-Hastings and Krewski 2016, van Doorn and Yu 2020). IAV predominantly infects the upper respiratory tract, causing mild to moderate symptoms of sore throat, fever, cough, fatigue, and potentially lethal secondary bacterial infection of the lower respiratory tract and pneumonia in high-risk individuals (Kalil and Thomas 2019, Wong and Lal 2023).
The first known pandemic, the 1918 Spanish flu, has racked up a notoriously high number of deaths at an estimated 50–100 million count. This was stupefying over the rest of the recorded influenza pandemic, with an average of 0.5–2 million recorded deaths (Saunders-Hastings and Krewski 2016). Animal reservoirs, such as swine and aquatic birds, are believed to drive the pandemic potential of IAV as it facilitates the phenomenon referred to as the ‘antigenic shift’ and ‘antigenic drift’ (Saunders-Hastings and Krewski 2016). Co-infection of avian and swine IAV in the reservoir facilitates the reassortment of the segmented influenza ribonucleic acid (RNA) genomes, causing a ‘shift’ in the HA and NA antigenic proteins of IAV, which partook in virus infection and release, potentially causing the emergence of new variants (Marshall et al. 2013, Ren et al. 2016). In addition, the lack of proofreading and high error rates of the viral RNA-dependent RNA polymerase of the virus causes an accumulation of mutations in the RNA genome of IAV, leading to a “drift” that produces antigenic variants of IAV (Wong and Lal 2023). Hence, these gave rise to the highly destructive variant of IAVs with great pandemic potential. Apart from that, the constantly evolving virus facilitates the development of drug resistance, further restricting the already limited treatment options (Shao et al. 2017). Currently, the United States Food and Drug Administration-approved antiviral drugs for IAV include the matrix protein 2 (M2) ion channel inhibitors (rimantadine, amantadine), NA inhibitors (oseltamivir, zanamivir), and polymeric acid protein endonuclease inhibitors (baloxavir marboxil). Of these, amantadine is no longer favoured due to the high prevalence of resistance among IAV strains (O’Hanlon and Shaw 2019, Lampejo 2020).
Urgent demand for novel and alternative therapeutic approaches
With the mounting issue of IAV drug resistance and pandemic scares, there is an urgent demand for novel and alternative therapeutic approaches against the IAV. Natural products, predominantly plants, have long been a rich source of compounds with therapeutic applications (El Sayed 2000, Musarra-Pizzo et al. 2021). Sourcing natural products for new antiviral drugs is not a novel concept. It has yielded successful outcomes such as oseltamivir, synthesized using quinic and shikimic acids as starting products (Zhang et al. 2020). Multiple in vitro studies have also shown potent antiviral activities of phytochemicals such as terpenoids, flavonoids, coumarins, polyphenols, and peptides against various human viruses, further proving the viability of investigating natural plant sources for anti-IAV therapeutics (Kurokawa et al. 2010, Musarra-Pizzo et al. 2021). Hence, this review aims to present and discuss the antiviral effects of natural plant extracts against IAV.
Potential natural antivirals against IAV
The medicinal usage of plant extracts is no stranger, with well-known plant derivative drugs such as aspirin, digitoxin, morphine, and atropine circulating in the market (Kurokawa et al. 2010, Musarra-Pizzo et al. 2021). Given the prosperous past accompanied by the excellent efficacy and minimal to no side effects of plant extracts against various viruses, this review covers the anti-IAV activities of various plant extracts. Using either in vitro or in vivo studies or a combination of both studies, certain plant extracts have been shown to be promising sources of anti-IAV therapeutics (Serkedjieva and Velcheva 2003, Droebner et al. 2007, Ehrhardt et al. 2007, 2013, Pu et al. 2009, Saha et al. 2010, Cecil et al. 2011, Liu et al. 2011, Wu et al. 2011, 2015, Zhang et al. 2013, Jin et al. 2020, Alahmad et al. 2022, Juárez-Méndez et al. 2022, Lim et al. 2024)
Excerpt: Conclusion:
MT, Baikal skullcap, SR, DA, Black elder, Purple coneflower, RG, and green tea have all proven to be potential candidates for anti-IAV therapy (Fig. 13).
Of these, the combination of purple coneflower and black elder was more effective than conventional antivirals such as oseltamivir (Tamiflu) for the early treatment against IAV through in vivo studies and clinical trials.