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Frontiers in Virology ·

Volume 6 - 2026 | https://doi.org/10.3389/fviro.2026.1897871

Antiviral potential of anthocyanins against SARS-CoV-2: current evidence, translational challenges, and future perspectives

  • Peter Lu1*corresponding author
  1. University of California, San Diego, La Jolla, CA, United States
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Abstract

Anthocyanins are naturally occurring flavonoids widely distributed in fruits, vegetables, and cereal grains that possess diverse biological activities, including antioxidant, anti-inflammatory, and antiviral properties. Since the emergence of the COVID-19 pandemic, increasing attention has been directed toward their potential to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This review summarizes current evidence regarding the antiviral activity of anthocyanins against SARS-CoV-2, with particular emphasis on their proposed molecular mechanisms and available experimental validation. Current studies indicate that anthocyanins may interfere with multiple stages of the viral life cycle through inhibition of the main protease (M pro), disruption of the spike–ACE2 interaction, and potential targeting of RNA-dependent RNA polymerase (RdRp) and helicase. In addition, anthocyanins may attenuate SARS-CoV-2-associated inflammation through modulation of host inflammatory pathways. While computational studies consistently support these proposed mechanisms, experimental evidence remains limited and is largely restricted to in vitro enzymatic and cell-based investigations. This review also discusses the low stability and bioavailability as a major translational challenge of anthocyanins and highlights current strategies, including structural modification and encapsulation, to improve their stability and therapeutic potential. Overall, anthocyanins represent promising natural compounds for further antiviral investigation; however, additional mechanistic studies, in vivo validation, and optimization of bioavailability are required before their clinical potential against COVID-19 can be established.

Keywords

1 Introduction

Flavonoids are a diverse class of naturally occurring polyphenolic compounds widely distributed in fruits, vegetables, and other plant-derived foods. Among the various flavonoid subclasses, anthocyanins are known for their abundance in the human diet and their diverse biological activities, including antioxidant, anti-inflammatory, and antiviral properties. In plants, anthocyanins are responsible for the characteristic pigmentation of many fruits, vegetables, and flowers, while increasing evidence suggests that they may also provide important health benefits in humans (1–4).

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), rapidly evolved into a global public health emergency following its emergence in late 2019, resulting in hundreds of millions of confirmed cases and deaths worldwide (5, 6). SARS-CoV-2 primarily infects the respiratory tract and causes a wide spectrum of clinical manifestations ranging from asymptomatic infection and mild respiratory illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ dysfunction, and death (6, 7) Although vaccines and antiviral therapies have substantially improved COVID-19 management, the continued emergence of viral variants and the need for complementary antiviral strategies have sustained interest in the identification of novel therapeutic candidates.

Anthocyanins have attracted research interest as potential antiviral candidates against SARS-CoV-2 because of their reported interference with multiple stages of the SARS-CoV-2 life cycle through interactions with several viral and host targets (8, 9). However, the available evidence remains fragmented, highlighting the need for a comprehensive synthesis and critical evaluation of available evidence. Thus, this review summarizes the current evidence regarding the antiviral activity of anthocyanins against SARS-CoV-2, with particular emphasis on their proposed molecular mechanisms, available experimental validation, and the major challenges in stability and bioavailability that limits clinical translation. In addition, the review discusses current strategies to improve anthocyanin stability and bioavailability and highlights future research directions required to facilitate their development as antiviral candidates.

The literature included in this review was identified through searches of major scientific databases, including PubMed, Scopus, and Web of Science. Only peer-reviewed articles published between 2019–2026 was considered for studies investigating the antiviral activity of anthocyanins against SARS-CoV-2 using computational, in vitro, in vivo, or clinical approaches; While additional literatures published between 2015–2026 concerning anthocyanin chemistry, stability, bioavailability, and COVID-19 were included to provide context for their potential therapeutic development.

2 Overview of anthocyanins

Anthocyanins are naturally occurring pigments responsible for the blue, red, and purple coloration of a wide variety of fruits, vegetables, flowers, and cereal grains. As members of the flavonoid family, these compounds exhibit various health benefits and have great potential to be applied in the food and pharmaceutical industries (1). Structurally, anthocyanins are based on a flavylium ion backbone with a C6-C3-C6 carbon structure, consisting of a 15-carbon skeleton with two aromatic rings (A and B) connected by a three-carbon bridge forming a heterocyclic ring (C) (10). Anthocyanidins are the aglycone, or sugar-free, forms of anthocyanins; therefore, the two groups are often discussed together in the scientific literature. Six major types of anthocyanidins: petunidin, malvidin, peonidin, cyanidin, delphinidin, and pelargonidin, accounts for 90% of anthocyanidins found in nature (11). The positively charged oxygen atom within the C ring distinguishes anthocyanidins from other flavonoids and contributes to their characteristic coloration and chemical reactivity. As the glycosylated forms of anthocyanidins, anthocyanins have one or more sugar molecules attached to their structure. This glycosylation occurs at specific hydroxyl groups, most commonly at the 3-position on the C-ring (12).

Anthocyanins are synthesized in plants as part of their secondary metabolism (12). Typical food source of anthocyanins includes fruits, such as berries and grapes; vegetables, such as eggplants and red cabbage; and grains or legumes, such as black rice and purple corns (13–15). The exact anthocyanin concentration and composition of different dietary sources vary significantly and depend highly on cultivation conditions. For instance, berry anthocyanins concentration is reported to range from 10 mg/100 g in wild strawberry to 772.4 mg/100 g in bilberry fresh weight (16).

Anthocyanins exhibit diverse biological activities, including antioxidant, anti-inflammatory, antiviral, neuroprotective, and anticancer effects (12, 17–19). Their antioxidant activity is largely attributed to their ability to scavenge reactive oxygen species (ROS) and reduce oxidative stress, while they also modulate multiple cellular pathways involved in inflammation and cell survival (15, 19). Increasing evidence further indicates that anthocyanins possess broad-spectrum antiviral activity against several RNA viruses by interfering with key stages of the viral life cycle, including viral entry, replication, and assembly. For example, anthocyanins have demonstrated inhibitory activity against influenza viruses through suppression of neuraminidase, an enzyme essential for viral release and transmission (20).

3 Current evidence of anthocyanins’ antiviral activity against SARS-CoV-2

Anthocyanins were identified early in the COVID-19 pandemic as potential therapeutic agents against SARS-CoV-2. Previous studies have reported the antiviral potential of flavonoids against several human pathogens, including SARS and MERS, both of which share significant genetic and structural similarities with SARS-CoV-2 (21). Current evidence of the antiviral activity of anthocyanins against SARS-CoV-2 according to the proposed antiviral mechanisms is summarized in Table 1.

Table 1. Summary of representative studies investigating the antiviral activity of anthocyanins against SARS-CoV-2.

Anthocyanins/extract investigatedProposed mechanismMethodologyPrincipal findingsRef.
118 Anthocyanin Derivatives (PhytoHub online database)Mpro, Spike, ACE2, RdRp, Helicasein silico:Molecular Docking (Schrödinger Glide on Maestro 11.5);Reference Compounds: Remdesivir, Hydroxychloroquine.- C3-D5G, C3GR, D3GG, and Nasunin exhibited strong multitarget binding (DS: -6.10 to -13.9);- C3GR exhibited strongest multitarget binding affinity (DS: -10.07 to -13.26).(22)
18 Anthocyanins (Major Compounds: C7A, P3R, P3G, C3A)Mpro (PDB: 6Lu7), Spike (PDB: 6lzg)in silico:Molecular Docking (AutoDock Tools 1.5.4); Pharmacokinetic ADME Analysis (SwissADME).- C7A, P3R, P3G exhibited strong binding to spike glycoprotein (DS: around -5.3);- C3A exhibited strong binding to Mpro (DS: -7.5);- No hepatocellular toxicity shown by C3A, C7A, P3R, P3G.(23)
10 Anthocyanins (PubChem database)Mpro (PDB: 6y84)in silico:Molecular Docking (MOE docking tool);Reference Compound: Remdesivir.- Leading compounds: Phacelianin, Gentiodelphin, Cyanodelphin, Tecophilin (DS: -30.02 to -36.30);- Polyacylated anthocyanins exhibited stronger Mpro binding than diacylated and monomeric anthocyanins.(24)
3,435 Anthocyanin Derivatives (PubChem database)Mpro (PDB: 6Lu7)in silico:Molecular Docking (Schrödinger Glide on Maestro 11.6); QikProp ADMET prediction;Reference Compound: N3-inhibitor- Leading Compounds: C3-6C, D3-3’DG5, D3S5G (DS: -9.58 to -12.37);- Stable interactions with catalytic residues His41 and Cys145.(25)
Pet3OG, Chrysanthemin, Peo3G, Oenin, Callistephin, MyrtillinMpro (PDB: 6M2N)in silico:Molecular docking (AutoDock Vina 1.1.2); ADMET prediction (ADMETlab 2.0);Reference compounds: Lopinavir, GC376, Baicalein.- All six investigated anthocyanins exhibited strong Mpro binding (DS: -8.3 to -8.6);- Pet3OG exhibited strongest Mpro binding (DS: -8.6);- ADMET analysis suggested favorable drug-likeness and no toxicity.(26)
C3S(Extracted from kokum fruit (Garcinia indica Choisy) for in vitro)Mpro (PDB: 6M03)in silico:Molecular docking (AutoDock v1.5.6)in vitro:SARS-CoV-2 Mpro inhibition assay (inhibitor assay kit); MTT cytotoxicity assay (BEAS-2B cells); Preparative HPLC isolation.Reference Compound: GC376in silico:- C3S exhibited strong binding with Mpro catalytic residues His41 and Cys145 (DS: -5.6);in vitro:- C3S inhibited Mpro activity by 62% at 50 μM and 79% at 100 μM of BEAS-2B cells;- No cytotoxicity to the cell is exhibited by C3S at 100 μM.(27)
C3G(Extracted from cranberry (Ardo) for in vitro)Mpro (PDB: 6LU7)in silico:Molecular docking screening of 250 cranberry phytochemicals;Molecular Dynamics simulation (200 ns) (GROMACS 2022)in vitro:FRET-based Mpro enzyme inhibition assay (Mpro assay kit).Reference Compound: GC376in silico:- C3G exhibiting highest docking affinity among screened cranberry phytochemicals (DS: -10.85)in vitro:- C3G inhibited recombinant SARS-CoV-2 Mpro (IC50: 9.98 μM);- Cranberry anthocyanin extracts inhibited Mpro (IC50: 23.58 μg/ mL), better than carotenoid and flavanol extracts.(28)
D3G(Extracted from blueberry (Vaccinium corymbosum L.) for in vitro)Mpro (PDB: 6M2N)in silico:Molecular docking (PLANTS software v1.2);HRMS-based metabolomics screening.in vitro:SARS-CoV-2 infection (Vero E6), qRT-PCR, plaque reduction assay; Reference compound: Baicalinin silico:- D3G was identified as a covalent Mpro inhibitor. (Δ;G: -34.32)in vitro:- D3G exhibited dose-dependent inhibition of SARS-CoV-2 replication in Vero E6 cells (IC50 = 35.8 ± 1.38 μM);- D3G (≥ 50 μM) completely inhibited viral infectivity in plaque reduction assays.(29)
C3R, P35D, D3R (Phenol-Explorer 3.6)RdRp (PDB: 7BV2)In silico:Molecular docking (Schrödinger Maestro 12.4); Molecular Dynamics simulation (100 ns)(GROMACS 2018.1)Reference compounds: Remdesivir-TP, ATP, TF3, Swertiapuniside.- C3R, P35D, and D3R were the leading anthocyanins for RdRp (MM-GBSA binding energies: −107.68, −99.18, and −90.70 kcal/mol)- C3R, P35D, and D3R formed stable interactions with catalytic residues Arg555 and U20 (RMSD ≈ 0.25 nm).(30)
Delphinidin, CyanidinSpike, Nucleocapsid, RdRpin vitro:EPM-based HEK293T transfection assay; SARS-CoV-2 infection assay (Vero E6); MTT cytotoxicity assay- Delphinidin and Cyanidin protected Vero E6 cells from SARS- CoV-2-induced cytopathic effects (EC50: 72.9, 72.5 μM);- Delphinidin and Cyanidin inhibited EPM-mediated expression of viral Spike, Nucleocapsid, and RdRp proteins;- Delphinidin and Cyanidin exhibited minimal cytotoxicity (CC50 > 400 μM).(31)
C3Glu, Peo3G(Purified from Black Rice (Oryza sativa L.) germ and bran extract)NLRP3 Inflammasomein vitro:Spike S1-induced inflammation in A549 lung epithelial cells and THP-1 macrophages; HPLC identification; Expression analysis (RT-qPCR); Cytokine Secretion analysis (ELISA).Reference compound: Dexamethasone- Black Rice extract (12.5-100 μg/mL) and purified C3Glu/Peo3G (1.25-10 μg/mL) suppressed Spike S1-induced NLRP3, IL-1β, and IL-18 expression; Reduced secretion of IL-6, IL-1β, and IL- 18 through inhibition of NF-κB/NLRP3 inflammasome signaling in A549 and THP-1 cells;- No cytotoxicity observed for Black Rice extract ≤ 200 μg/mL and C3Glu/Peo3G ≤ 20 μg/mL.(32)
European black elderberry (Sambucus nigra) extracts (4.6% total polyphenols, 3.5% anthocyanins)Post-entry viral replicationin vitro:HPLC characterization; SARS-CoV-2 infection (Calu-3, Caco-2); Viral replication assay (qRT-PCR); WST-1 cytotoxicity assay; Time-of-addition assay.Reference compound: Remdesivir- Extract inhibited replication of SARS-CoV-2 Wuhan strain and Alpha, Beta, Gamma, Delta, and Omicron variants (IC50 ≈ 1:200- 1:800; IC90 ≈ 1:100) with minimal cytotoxicity;- HPLC-based Estimated IC50 values against Wuhan strain: C3S5G 6 μM, C3S 35 μM, C3Glu 41 μM;- Time-of-addition assays indicated inhibition occurs after viral entry.(33)
European black elderberry (Sambucus nigra) extract (3.2% anthocyanins)Viral replication; synergistic antiviral activity with quininein vitro:SARS-CoV-2 infection (Calu-3); Viral replication assay (qRT-PCR); WST-1 cytotoxicity assay; Bliss independence model (SynergyFinder)- Combined treatment with 1 μM quinine inhibits viral replication completely (Extract dilution: 1:3200-1:800).- Strong synergistic with quinine antiviral activity (Bliss synergy score = 27.8) against Wuhan type SARS-CoV-2.(34)

Representative computational and experimental studies evaluating the antiviral potential of anthocyanins against SARS-CoV-2 are summarized according to the anthocyanin(s) or extract investigated, study type, proposed antiviral mechanism, experimental methodology, and principal findings. Experimental methodology includes the computational software, molecular targets, reference compounds, cell models, or analytical techniques used, where applicable. Principal findings summarize the major relevant quantitative or qualitative outcomes reported in each study.

Mpro, main protease (3CLpro); RdRp, RNA-dependent RNA polymerase; ACE2, angiotensin-converting enzyme 2; DS, Docking Score; ADME, absorption, metabolism, excretion, and distribution; ADMET, Absorption, Distribution, Metabolism, Excretion, and Toxicity; HPLC, High Performance Liquid Chromatography; HRMS, high-resolution mass spectrometry; EPM, exosome–polyethylenimine-based gene delivery matrix; FRET, fluorescence resonance energy transfer; EC50, half-maximal effective concentration; IC50, half-maximal inhibitory concentration; C3-D5G, cyanidin 3-(p-coumaroyl)-diglucoside-5-glucoside; C3GR, cyanidin 3-O-glucosyl-rutinosidel; D3GG, delphinidin 3-O-glucosyl-glucoside; C3A, cyanidin-3-arabinoside; P3R, pelargonidin-3-rhamnoside; P3G, pelargonidin-3-glucoside; C7A, cyanidin-7-arabinoside; D3S5G, Delphinidin 3-sambubioside-5-glucoside; D3-3’DG5, Delphinidin 3,3’-di-glucoside-5-(6-p-coumarylglucoside); C3-6C, Cyanidin 3-(6’’-p-coumarylsambubioside); Peo3G, Peonidin-3-O-glucoside; Pet3G, Petunidin 3-O-glucoside; C3S, Cyanidin-3-O-sambubioside; C3G, cyanidin 3-O-galactoside; D3G, Delphinidin-3-glucoside; C3Glu, cyanidin-3-O-glucoside; Peo3G, Peonidin-3-O-glucoside; C3S5G, Cyanidin-3-sambubioside-5-glucoside; C3R, Cyanidin3-O-rutinoside; P35D, Petunidin 3,5-O-diglucoside; D3R, Delphinidin 3-O-rutinoside.

3.1 Targeting SARS-CoV-2 main protease (Mpro)

SARS-CoV-2 main protease (Mpro), also known as 3-chymotrypsin-like protease (3CLpro), is responsible for cleaving viral polyproteins into functional proteins required for viral replication and maturation. Because human protease is structurally different, Mpro has become one of the most attractive molecular targets for the development of antiviral agents against COVID-19 (35, 36). Therefore, numerous studies have investigated the ability of anthocyanins to interact with the catalytic site of Mpro using computational approaches, with several studies subsequently providing preliminary experimental validation.

Collectively, computational evidence consistently identifies Mpro as the primary molecular target of anthocyanins against SARS-CoV-2. Numerous independent molecular docking studies have demonstrated favorable interactions between structurally diverse anthocyanins and Mpro, especially with the catalytic residues His41 and Cys145. Among the anthocyanins investigated, multiple cyanidin-, delphinidin-, pelargonidin-, petunidin-, malvidin-, and peonidin- derivatives have all demonstrated favorable predicted binding affinities toward Mpro across multiple independent investigations with no clear cellular cytotoxicity reported (22–26). Notably, polyacylated anthocyanins, including tecophilin cyanodelphin, gentiodelphin, and phacelianin, consistently exhibited stronger predicted interactions than diacylated or monomeric anthocyanins, suggesting that structural modification may enhance inhibitory activity (24).

Although molecular docking provides valuable insight into potential protein–ligand interactions, in vitro experimental validation is essential to confirm such bindings. Several studies have begun to provide such evidence. Cyanidin-3-O-sambubioside (C3S) isolated from kokum fruit demonstrated approximately 79% inhibition on Mpro activity at a concentration of 100 μM in an in vitro enzymatic study using the Mpro inhibitor assay kit and showed favorable binding to the catalytic residues His41 and Cys145 of Mpro in in silico docking (27). Similarly, cyanidin 3-O-galactoside isolated from cranberry exhibited potent Mpro inhibition with an IC50 value of 9.98 μM in in vitro Fluorescence Resonance Energy Transfer (FRET) enzymatic assays, while general frozen cranberry anthocyanin extracts demonstrated an overall IC50 value of 23.58 μg/mL against the viral protease (28). More recently, a high-resolution mass spectrometry (HRMS)-based screening platform identified delphinidin-3-glucoside as a covalent Mpro inhibitor. In addition to computational support, this compound produced dose-dependent inhibition of SARS-CoV-2 infection in Vero E6 cells with an IC50 value of approximately 35.8 μM, which is comparable to that of the established Mpro inhibitor baicalin (29).

Overall, the available evidence consistently identifies Mpro as the most extensively investigated molecular target of anthocyanins against SARS-CoV-2. While majority of the current evidence remains theoretical computational predictions, several preliminary enzymatic and cell-based experiments provide positive evidence to support anthocyanin’s predicted binding activity with Mpro. As current evidence remains largely preclinical, further investigations involving animal models, pharmacokinetic studies, and clinical trials are required to determine whether inhibition of Mpro by anthocyanins can be translated into meaningful antiviral efficacy in vivo.

3.2 Targeting other viral replication proteins

Beyond Mpro, anthocyanins have also been proposed to interact with other SARS-CoV-2 proteins involved in viral replication, particularly RNA-dependent RNA polymerase (RdRp) and helicase. These proteins play essential roles in viral RNA synthesis and genome replication, making them attractive antiviral targets (37).

A comprehensive virtual screening study investigating naturally occurring polyphenols against SARS-CoV-2 RdRp identified several anthocyanins as promising inhibitors of viral RNA synthesis. Among the screened compounds, cyanidin-3-O-rutinoside, petunidin-3,5-O-diglucoside, and delphinidin-3-O-rutinoside demonstrated the strongest predicted interactions with the RdRp catalytic site, exhibiting greater binding energies than the reference antiviral remdesivir (30). These findings are supported by a multitarget molecular docking study, in which cyanidin-3-O-glucosyl-rutinoside demonstrated strong predicted binding across multiple SARS-CoV-2 proteins, including RdRp, Mpro, and helicase with docking scores of -10.1 and -10.93 (22). Such multitarget interactions suggest that certain anthocyanins may possess multitarget antiviral properties capable of simultaneously interfering with multiple stages of the SARS-CoV-2 life cycle.

To provide preliminary experimental support for these computational predictions, an Exosome–Polyethylenimine-based Gene delivery matrix (EPM) was developed as a biosafety level 2-compatible platform for evaluating antiviral polyphenols against SARS-CoV-2 (31). This platform facilitates the expression of viral proteins, including spike, nucleocapsid, and RdRp, in HEK293T cells, enabling rapid screening of candidate compounds. Anthocyanidins delphinidin and cyanidin, sugar-free forms of anthocyanin, are shown to protected Vero E6 cells from SARS-CoV-2-induced cytopathic effects using this system, exhibiting EC50 values of approximately 72 μM (31). However, this study did not directly demonstrate inhibition of RdRp or other individual viral proteins and therefore provides only indirect support for the proposed multitarget mechanism.

Compared with Mpro, considerably fewer studies have investigated these proteins, and the available evidence is largely limited to computational predictions. To date, no studies have conclusively demonstrated direct inhibition of these proteins through enzymatic or structural assays, emphasizing the need of such experimental validation to support the predicted interaction between anthocyanins and multiple SARS-CoV-2 target proteins and in vivo validation using animal models are required before concluding anthocyanins as multitarget SARS-CoV-2 antivirals.

3.3 Targeting viral entry through spike–ACE2 interaction

Apart from targeting viral replication proteins, several studies have suggested that anthocyanins may also interfere with early stage of the viral entry into host cells. The viral entry process is initiated through the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein to the Angiotensin-Converting Enzyme 2 (ACE2) receptor (38). Consequently, disruption of the spike–ACE2 interaction has been widely recognized as a promising antiviral strategy, as it may prevent viral attachment and subsequent infection (39).

Current computational studies suggest that several anthocyanins may interact with both the spike glycoprotein and ACE2, thereby potentially disrupting viral attachment. In the large-scale multitarget molecular docking study, cyanidin 3-O-glucosyl-rutinoside demonstrated the strongest predicted interactions with both spike protein and ACE2, exhibiting docking scores of -10.07 and -13.26, respectively, outperforming the reference compounds remdesivir and hydroxychloroquine (22). Additionally, pelargonidin-3-rhamnoside, pelargonidin-3-glucoside, and cyanidin-7-arabinoside were also predicted to interact favorably with the receptor-binding domain of the spike glycoprotein with docking scores around -5.3, indicating possible interference with the interaction between the viral spike protein and the ACE2 receptor (23).

Current computational evidence suggests that several anthocyanins may inhibit SARS-CoV-2 entry by disrupting interactions between the viral spike glycoprotein and the ACE2 receptor. However, experimental evidence supporting this mechanism remains scarce. Consequently, the proposed inhibition of viral entry should currently be regarded as a computational prediction that requires validation through biochemical assays and cell-based infection models before its biological relevance can be established.

3.4 Modulation of host inflammatory responses

In addition to directly targeting viral proteins, anthocyanins may exert antiviral benefits by modulating host inflammatory responses. Excessive activation of the inflammatory cytokines has been associated with the severity of COVID-19 symptoms and contributes substantially to tissue damage and disease progression (40). Therefore, compounds capable of regulating these host responses may complement direct antiviral strategies by reducing inflammation-associated pathology.

Current evidence supporting this mechanism is limited. Using an in vitro model of SARS-CoV-2 spike protein-induced inflammation, black rice (Oryza sativa L.) germ and bran extract rich in anthocyanins, together with its major constituents cyanidin-3-O-glucoside and peonidin-3-O-glucoside, significantly suppressed the expression of the inflammatory genes NLRP3, IL-1β, and IL-18, while reducing the secretion of the pro-inflammatory cytokines IL-6, IL-1β, and IL-18 in A549 and THP-1 cells. The extract was effective at concentrations of 12.5–100 μg/mL, whereas purified C3G and P3G exhibited anti-inflammatory activity at 1.25–10 μg/mL, suggesting that these anthocyanins may attenuate SARS-CoV-2 associated inflammatory responses through inhibition of the NF-κB/NLRP3 signaling pathway (32).

Unlike Mpro inhibition or disruption of the spike-ACE2 interaction, modulation of host inflammatory pathways does not directly suppress viral replication but instead targets the host response to infection. Therefore, although the available evidence indicates that anthocyanins may alleviate inflammation associated with COVID-19, their anti-inflammatory activity should be considered complementary to, rather than a substitute for, direct antiviral mechanisms.

3.5 Evidence from anthocyanin-rich elderberry extracts

In addition to investigations using purified anthocyanins, several studies have evaluated anthocyanin-rich plant extracts for their antiviral activity against SARS-CoV-2 instead of using purified anthocyanins. Such studies may better reflect the biological effects of dietary anthocyanin consumption because the compounds are evaluated within their natural food matrix, where interactions with other bioactive constituents may influence antiviral activity.

Among these, standardized European black elderberry (Sambucus nigra L.) fruit extract has received considerable attention because of its high anthocyanin content, particularly cyanidin-3-glucoside (41). An in vitro study using a European black elderberry extract standardized to contain 4.6% total polyphenols and 3.5% anthocyanins demonstrated antiviral activity against the original Wuhan strain of SARS-CoV-2 as well as the Alpha, Beta, Gamma, Delta, and Omicron variants; With cyanidin-3-sambubioside-5-glucoside exhibiting strongest inhibition for all variants (IC50: 6-24 µM) among major anthocyanin components in the extract (33). Building upon these findings, a subsequent study evaluated the combined antiviral effects of elderberry extract standardized to 3.2% anthocyanins with quinine against both Influenza A virus and SARS-CoV-2 (34). Using SARS-CoV-2-infected human Calu-3 lung epithelial cells, the combination reduced viral replication without affecting cell viability, as determined by quantitative RT-PCR and WST-1 assays respectively. Furthermore, synergistic antiviral effects were observed, with a Bliss independence score of 27.8 against SARS-CoV-2, suggesting that anthocyanin-rich extracts may enhance antiviral efficacy when combined with other bioactive compounds (34).

Collectively, these studies provide preliminary experimental evidence supporting the antiviral activity of anthocyanin-rich extracts against SARS-CoV-2 replication overall instead of a specific mechanism. Nevertheless, because the extracts contain multiple polyphenols and other phytochemicals, the relative contribution of anthocyanins to the observed antiviral effects may arise from the combined actions of multiple constituents rather than anthocyanins alone and cannot be determined with certainty. Future studies using purified compounds, standardized extract compositions, and mechanistic analyses will therefore be important to clarify the specific role of anthocyanins and to determine whether synergistic interactions among extract constituents contribute to their antiviral activity.

4 Challenges to clinical translation and potential solutions

Despite encouraging computational and preclinical evidence, several challenges currently limit the clinical translation of anthocyanins as antiviral candidates against SARS-CoV-2. Anthocyanins exhibit poor physicochemical stability and low bioavailability, with only approximately 2% of anthocyanins reported to retain their intact C6–C3–C6 structure after ingestion, which substantially reduce their therapeutic potential (15). Thus, improving the stability, delivery, and systemic availability of anthocyanins remains an important area of research.

Anthocyanins are highly susceptible to degradation by environmental factors, particularly pH, temperature, oxygen, and light (42). Under acidic conditions, anthocyanins predominantly exist as red flavylium cation. Whereas neutral and alkaline environments promote structural transformations such as electron donations to form quinonoidal bases, reducing both their stability and biological activity. Therefore, such degradation may occur during food processing, storage, gastrointestinal digestion, and systemic absorption, potentially limiting the concentrations required to achieve the antiviral effects reported in vitro (43).

Several approaches have been shown to be effective in protecting anthocyanins from external environmental conditions. These strategies include structural modification through glycosylation and acylation, physical protection through encapsulation, stabilization via complex formation with macromolecules, and the application of co-pigmentation techniques. These approaches minimize degradation to enhance anthocyanins’ stability, preserving their structural integrity and functional properties (4, 43).

Encapsulating anthocyanins can significantly increase their bioavailability by protecting them from certain extreme environments within the human body for optimal absorption, such as allowing the chemicals to reach the small intestine intact after the gastrointestinal tract. Encapsulation technologies, such as microencapsulation and nanoencapsulation, involves coating extracted bioactive compounds with protective materials to improve their stability and functionality (44). The resulting particles can range from micro to nano sizes, depending on the techniques and parameters used. Generally, microencapsulation techniques are categorized into three groups: physical methods (spray and freeze drying), chemical methods (interfacial polymerization and molecular inclusion complexation), and physicochemical methods (coacervation and ionic gelation) (44, 45). Since these encapsulated particles are intended for use in the food industry and may enter the human body, the carrier agents must be classified as Generally Recognized as Safe (GRAS). Biopolymers composed of proteins, carbohydrates, or their combinations are among the most commonly used encapsulating agents (46). Nanoparticles have attracted particular interest because their high surface-area-to-volume ratio can enhance the stability, solubility, and bioavailability of bioactive compounds while providing more reactive sites for interaction. Furthermore, the selection of appropriate wall materials is critical and should be based on the physicochemical properties of the target compound. For example, whether a compound is hydrophilic or hydrophobic plays a key role in determining the most suitable encapsulation strategy and carrier material (47).

There are various techniques for producing nanocarriers, including nanoprecipitation, spray drying, freeze drying, complex coacervation, and ionic gelation. Additionally, methods such as high-pressure homogenization, ultrasonication, and ultra-high pressure are also used to encapsulate bioactive substances (47). Studies have shown that the physical properties of the final microcapsules are significantly impacted by the choice of wall material, which in turn affects the degradation of anthocyanins. For instance, the degradation of anthocyanins tends to accelerate with higher moisture content in microcapsules (43).

Extracting and isolating anthocyanins from natural plant tissues is a crucial and complex process to ensure stability and purity of extract; As the isolation process is not selective, and unwanted by-products can lead to the degradation of anthocyanins, extraction capacity and efficiency can be easily influenced (48). Therefore, extraction of anthocyanins are often followed by extension and modification so these compounds can be applied in practice. Traditional methods like soaking, stirring, enzymatic extraction, and ultrasound-assisted extraction are commonly utilized, while the most prevalent methods for extracting anthocyanins involve solvents, enzymes, and ultrasound (49).

5 Conclusion and future perspectives

Anthocyanins are naturally occurring flavonoids that have attracted attention as potential antiviral candidates against SARS-CoV-2 because of their diverse biological activities and widespread availability in the human diet. This review summarized the current evidence supporting their antiviral potential, highlighting multiple proposed mechanisms of action, including inhibition of key viral entry and replication proteins, modulation of host inflammatory responses, and the antiviral activity of anthocyanin-rich plant extracts. Collectively, these findings suggest that anthocyanins may represent a potential class of natural compounds for further antiviral investigation.

Despite these encouraging findings, the current evidence remains insufficient to establish anthocyanins as effective antiviral therapies against SARS-CoV-2. Most available studies rely on computational molecular docking analyses or in vitro models, with relatively few investigations providing comprehensive mechanistic validation or evaluating antiviral efficacy clinically or in vivo. Furthermore, although interest in anthocyanins as potential anti-SARS-CoV-2 agents increased rapidly during the COVID-19 pandemic, relatively few subsequent studies have expanded or experimentally validated the initial findings, limiting the strength of the current evidence base. In addition to low bioavailability and stability, differences in anthocyanin composition, experimental design, and anthocyanin source make direct comparisons among studies difficult and are also important barriers to clinical translation. Therefore, although current findings support continued investigation of anthocyanins, their therapeutic potential should be interpreted with appropriate caution.

Future research should prioritize the development of strategies to improve the stability and bioavailability of anthocyanins, appropriate safety evaluations, alongside comprehensive pharmacokinetic evaluations and mechanistic studies, to enhance their translational potential as antiviral candidates. In addition, well-designed animal studies and clinical trials are needed to determine whether the antiviral activities observed in computational and in vitro investigations can be translated into meaningful clinical benefit. By addressing these challenges, anthocyanins may contribute to the development of future antiviral interventions against SARS-CoV-2.

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Footnotes

Edited by: Arif Nur Muhammad Ansori, Virtual Research Center for Bioinformatics and Biotechnology, Indonesia

Reviewed by: Dr. Prashant Kumar Tiwari, Parul University, India

Saurabh Dilip Bhandare, “Laboratorium Scientiae et Studiorum Investigativorum. India

Muhammad Maaz, Bahauddin Zakariya University, Pakistan

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

PL: Writing – original draft, Writing – review & editing.

References

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Citation

Lu, P. (2026). Antiviral potential of anthocyanins against SARS-CoV-2: current evidence, translational challenges, and future perspectives. Frontiers in Virology, Volume 6. https://doi.org/
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6 - 2026

Copyright

Copyright © 2026 Lu.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Peter Lu

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