Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents

Abstract

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field.

Keywords: broad-spectrum anti-viral; epigenetic modifications; plant-derived substances; virus.

Figure 1

DNA methylation and its modulation of gene expression. Transcription factors recognize gene promoter and bring RNA polymerase to transcript the gene (A); DNA methylation at CpG island switch on/off gene according to the locus where methylation occurs (B).

Figure 2

Nucleosome structure and histone modifications. The amino acids chain includes functional groups at specific amino acid residues (histone tails) which modify the interaction between DNA and histones (left); acetylation of histone N-terminal tails facilitates the transcription initiation (right).

Figure 3

MicroRNA synthesis, translational repression, and degradation of mRNA. MiRNAs are transcribed by RNA polymerase (Pol II), processed by DROSHA and DGCR8 to obtain pre-miRNA; pre-miRNA is transported to the cytosol where DICER enzyme, together with other proteins, processes the miRNA into a single-strand RNA which is incorporated into RISC complex and binds Argonaute. The interaction of miRNA with mRNA is followed by mRNA decay and translational repression.

Figure 4

Viral infection and epigenetic machinery. Viral infection affects global DNA methylation and the expression and activity of DNMTs. In addition, viral infection affects global histone modifications and modulates the expression and activity of HAT and HDAC. Viral infection also modulates the expression of miRNA, which is required to evade immune response and to promote viral replication.

Figure 5

Anti-viral activity of curcumin. The figure shows the broad spectrum of antiviral activity of curcumin, which attacks most of the viruses studied.

Figure 6

Anti-viral activity of EGCG against IAV, HPV, and HCV viruses. HCV replication dependent on host CD81 and host miR-122. EGCG upregulated miR-548m expression, which in turn regulates CD81 expression and downregulates miR-122 (also mediated by other bioactive substances such as resveratrol) to exert anti-HCV activity. IAV infection caused a significant decrease in microRNA let-7 expression which is required for regulating expression of type I interferon. EGCG and other bioactive substances, such as quercetin, upregulate let-7 to increase interferon expression and effectively inhibit IAV infection.

Figure 7

Natural bioactive substances with epigenetic modifying activity. Shows plant-derived bioactive compounds that modulate DNA methylation (left), histone medication (middle), and miRNA expression (right).