Antiviral treatment for viral pneumonia: current drugs and natural compounds | Virology Journal

When discussing effective treatment strategies for viral pneumonia, besides traditional antiviral drugs, natural components are increasingly gaining attention as adjuvant therapies. These natural components not only possess potential antiviral activity but can,also enhance the body’s immune response, providing additional protection for patients [8, 70]. Table 2 is about natural compounds and their antiviral mechanisms. Here are several natural antiviral components that research has shown to be effective against viral pneumonia:

Astragalus IV

Astragalus membranaceus is one of the most widely used traditional Chinese herbs. It serves as an immunostimulant, tonic, antioxidant, hepatoprotectant, diuretic, antidiabetic, anticancer, and expectorant [71, 72]. Astragaloside IV (AS-IV), the most active monomer in Astragalus, exhibits extensive antiviral, anti-inflammatory, and antifibrotic pharmacological effects, showing protective effects in acute lung injury [73]. Studies have shown that AS-IV inhibits the production of reactive oxygen species (ROS) in a dose-dependent manner in A549 cells infected with influenza virus, thereby inhibiting the activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and Caspase-1, reducing the secretion of interleukin (IL)-1β and IL-18. In BALB/c mice infected with Poly(I:C), oral administration of AS-IV significantly alleviates Poly(I:C)-induced acute pneumonia and pulmonary pathology [74]. Additionally, astragaloside can reduce lung inflammation in rats by inhibiting the TGF-β1/Smad pathway [75]. This indicates that astragaloside has potential in the treatment of viral pneumonia.These studies indicate that Astragalus membranaceus and its active component, AS-IV, may be a significant source for developing new antiviral drugs or as an adjuvant therapy for viral respiratory diseases. They not only enhance immune system function but also provide direct protective effects during viral infections, mitigating inflammatory responses and tissue damage.

Houttuynia cordata flavonoids and polysaccharides

Houttuynia cordata is a classic Traditional Chinese Medicine (TCM) used clinically for the treatment of pneumonia [76, 77]. Total flavonoids (HCF) and polysaccharides (HCP) are key medicinal components of Houttuynia cordata in the treatment of viral pneumonia [78]. Research has shown that flavonoids in Houttuynia cordata can alleviate acute lung injury induced by H1N1 in mice by inhibiting influenza virus and Toll-like receptor signaling [79]. For lethal H1N1 infections in mice, the combination of HCF and HCP significantly increased survival rates and extended lifespan compared to monotherapy. The combined use of HCF and HCP can markedly improve symptoms of viral pneumonia, manifested by reduced lung indices, more intact lung tissue morphology, decreased inflammatory cells and mediators. Moreover, the combination of HCF and HCP can regulate gut microbiota, significantly reducing the proportion of pathogenic Enterobacteriaceae and pro-inflammatory cytokine secretion, demonstrating synergistic effects in reducing lung and gut damage [80, 81]. A 70% ethanol extract from the aerial parts of Houttuynia cordata inhibited the production of inflammatory biomarkers IL-6 and NO in lung epithelial cells (A549) and alveolar macrophages (MH-S). Oral administration of the same plant material (100 and 400 mg/kg) significantly inhibited the pulmonary inflammatory response in a lipopolysaccharide (LPS)-induced acute lung injury model in mice. Major flavonoid compounds were successfully isolated from the extract, which also alleviated LPS-induced pulmonary inflammation in mice when administered orally [82]. Additionally, studies on the effects of flavonoids from Houttuynia cordata revealed that hyperoside, quercitrin, and quercetin were more effective against H1N1 infection than HCF [83]. This suggests that the combination of flavonoids and polysaccharides from Houttuynia cordata holds advantages in the treatment of viral pneumonia. These research findings indicate that Houttuynia cordata and its active components, particularly flavonoids and polysaccharides, show promising potential in the treatment of viral pneumonia. They not only enhance immune system function but also directly combat viral infections, reduce inflammatory responses, and further protect lung and gut health by modulating the gut microbiota. However, although the preliminary results are very encouraging, more clinical trials are needed to verify the safety and efficacy of Houttuynia cordata and its extracts before they can be applied in clinical treatments.

Theaflavin-3′-gallate

Theaflavin-3′-gallate (T3G) is a monomer of theaflavins found in black tea and is considered an important bioactive component beneficial to health [84]. Theaflavin-3′-gallate (T3G) and theaflavin (TF1) can effectively inhibit the replication of influenza viruses such as H1N1-UI182, H1N1-PR8, H3N2, and H5N1, with T3G demonstrating the most significant antiviral activity in vivo. Intraperitoneal injection of 40 mg/kg/day T3G effectively alleviated viral pneumonia, maintained body weight, and increased the survival rate of mice infected with a lethal dose of H1N1-UI182 to 55.56%. Peripheral blood hematological analysis further showed that T3G increased lymphocyte counts and decreased neutrophil, monocyte, and platelet counts in infected mice. RT-qPCR results indicated that T3G reduced the mRNA expression levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β), chemokines (CXCL-2 and CCL-3), and interferons (IFN-α and IFN-γ) post-influenza virus infection. Additionally, T3G significantly downregulated the expression levels of TLR4, p-p38, p-ERK, and cytokines IL-6, TNF-α, IL-1β, and IL-10 [85]. Studies indicate that T3G binds tightly to the SARS-CoV-2 spike protein RBD with a very low KD value of 1.3 nM, suggesting it could disrupt ACE2 binding, potentially preventing viral entry. T3G also blocks the main protease (Mpro) of SARS-CoV-2 with an IC50 of 18.48 μM and has been shown to reduce viral load by 75% under laboratory conditions [86]. These findings suggest that T3G not only significantly inhibits viral replication and proliferation in vitro but also mitigates pneumonia damage in vivo. Its antiviral effects may be attributed to the downregulation of influenza virus-induced inflammatory cytokines via modulation of the TLR4/MAPK/p38 signaling pathway.These research findings indicate that T3G has potential applications in combating a variety of viruses, including influenza viruses and SARS-CoV-2. It not only exhibits strong antiviral activity but also reduces inflammatory damage by modulating the immune response.

Berberine

Berberine is a natural isoquinoline alkaloid isolated from plants of the Berberis genus, known for its diverse biological properties including anti-inflammatory, antibacterial, antifungal, and anthelmintic effects [87, 88]. Studies have shown that berberine strongly inhibits the replication of Influenza A virus A/FM1/1/47 (H1N1) in A549 cells and in mouse lungs. Additionally, berberine alleviated lung inflammation in mice compared to those treated with a vehicle, reducing necrosis, inflammatory cell infiltration, and pulmonary edema caused by viral infection. Berberine suppressed the upregulation of the TLR7 signaling pathway (such as TLR7, MyD88, and NF-κB (p65)) induced by viral infection at both the mRNA and protein levels. Furthermore, berberine significantly inhibited the increase in the Th1/Th2 and Th17/Treg ratios and the production of inflammatory cytokines induced by viral infection [89]. These findings suggest that berberine may improve lung inflammation in mice with influenza viral pneumonia by inhibiting NLRP3 inflammasome activation and pyroptosis mediated by GSDMD. Another study indicates that berberine primarily exerts therapeutic effects on lung fibrosis associated with COVID-19 pneumonia by regulating cell proliferation, metabolism, and survival via tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and chemokine (C–C motif) ligand 2 (CCL2) [90]. In mouse experiments, berberine reduced the mortality rate from 90 to 55% and decreased the viral titer in the lungs two days post-infection (P P P P P P 91].These results indicate that Berberine combats viral infections through multiple mechanisms. It not only demonstrates strong antiviral activity but also reduces inflammatory damage by modulating the immune response.

Paeoniflorin

Paeoniflorin is an herbal component derived from the root of Paeonia lactiflora. It is used in traditional Chinese medicine for its antispasmodic and analgesic properties and is known for its anticoagulant, neuromuscular blocking, cognitive enhancement, immunomodulatory, and antihyperglycemic effects [92]. Paeoniflorin (at doses of 50 and 100 mg/kg) can alleviate acute lung injury induced by Influenza A Virus (IAV). It reduces pulmonary edema, improves lung tissue pathology, and decreases the accumulation of inflammatory cells in the lungs. Results show that paeoniflorin (50 and 100 mg/kg) can ameliorate acute lung injury induced by IAV, increasing the survival rate of infected mice (by 40% and 50%, respectively), lowering the viral titer in lung tissues, improving histological changes, and reducing lung inflammation. Paeoniflorin also decreases the levels of pulmonary fibrosis markers (type IV collagen, α-smooth muscle actin, hyaluronic acid, laminin, and procollagen III) and downregulates the expression levels of type I collagen (Col I) and type III collagen (Col III) in lung tissues, thus improving pulmonary fibrosis. Additionally, paeoniflorin inhibits the expression of αvβ3, TGF-β1, Smad2, NF-κB, and p38MAPK in lung tissues [93].

The combination of carboxymethyl chitosan and dextran sulfate (CS-DS) exhibited synergistic effects in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Two compounds identified through network pharmacology screening, paeoniflorin and luteolin, significantly reduced the expression levels of reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in LPS-stimulated RAW264.7 cells. In the LPS-induced ALI model, the combination of paeoniflorin and luteolin similarly reduced the expression of inflammatory factors and oxidative stress levels. Furthermore, the expression of proteins involved in the LPS-activated NF-κB and MAPK signaling pathways was effectively inhibited by this combination therapy [94].Paeoniflorin demonstrates significant efficacy in combating viral infections and acute lung injury through multiple mechanisms. Not only does it directly inhibit viral replication, but it also protects lung health by modulating immune responses, reducing inflammation, and improving pulmonary fibrosis. Particularly, the combined use of Paeoniflorin and Luteolin in LPS-induced acute lung injury models exhibits stronger anti-inflammatory and antioxidant effects, suggesting that this combination therapy may become an effective strategy for treating acute lung injury in the future.

Patchouli alcohol

Patchoulol is a tricyclic sesquiterpene extracted from Agastache rugosa and has been traditionally used in Chinese medicine to treat inflammatory conditions [95]. Patchoulol exhibits various pharmacological activities, including antiemetic, anti-inflammatory, antibacterial, and antiviral properties [96]. It has been confirmed that patchoulol can interact specifically with HA2, preventing the fusion of the viral membrane with intracellular membranes, thereby inhibiting the early life cycle of influenza A viruses [97]. When evaluated for its anti-influenza virus activity against A/PR/8/34 using a plaque formation assay, patchoulol reduced plaque numbers by 75% at 2 μg/mL and by 89% at 10 μg/mL. Patchoulol demonstrates dose-dependent antiviral activity against influenza A viruses, with an estimated IC50 value of 2.635 μM [98]. Research indicates that the oral administration of patchoulol appears to enhance protection against influenza virus infection in mice by boosting the host’s immune response and dampening systemic and pulmonary inflammatory responses. Patchoulol primarily inhibits influenza A (H2N2) virus by interfering with the function of viral neuraminidase. It was found that patchoulol can inhibit the replication of different influenza A viruses in vitro, with pandemic H1N1 virus (Vir09) being the most sensitive to patchoulol treatment (IC50 99]. Therefore, patchoulol is worthy of further investigation as a novel anti-IAV drug candidate in future research.Patchoulol demonstrates considerable potential in combating influenza viruses, particularly in inhibiting viral replication, enhancing immune responses, and reducing inflammation. Therefore, Patchoulol warrants further in-depth research as a novel candidate for anti-IAV drugs to evaluate its feasibility and safety for clinical applications.

Emodin

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a natural anthraquinone compound [100], derived from various traditional Chinese medicinal plants such as Polygonum multiflorum, Rheum palmatum, and Polygonum cuspidatum, known for its antioxidant, anti-inflammatory, immunosuppressive, antiviral, and antitumor activities [101, 102]. Emodin also inhibits infections by Coxsackie virus (CV), human respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV) [103]. Studies have shown that emodin can significantly inhibit the replication of Influenza A Virus (IAV, ST169, H1N1), decrease IAV-induced expression of TLR2/3/4/7, MyD88, and TRAF6, and reduce IAV-induced phosphorylation of p38/JNK MAPK and nuclear translocation of NF-κB p65. Emodin can also activate the Nrf2 pathway, lower ROS levels, increase GSH levels and the GSH/GSSG ratio, and upregulate the activity of SOD, GR, CAT, and GSH-Px. Knockdown of Nrf2 by siRNA significantly blocks the inhibitory effect of emodin on IAV-induced activation of the TLR4, p38/JNK, and NF-κB pathways, as well as IAV-induced production of IL-1β, IL-6, and IAV M2 protein expression. Emodin also significantly increased the survival rate of mice, alleviated pulmonary edema and lung viral titers, and improved lung histopathological changes [104]. Additionally, emodin can significantly inhibit IAV replication and IAV-mediated inflammation, with its mechanism possibly related to the activation of the Nrf2 signaling pathway and inhibition of IAV-induced oxidative stress, TLR4, p38/JNK MAPK, and NF-κB pathway activation [104]. Emodin demonstrates extensive potential in combating influenza virus infections, particularly in inhibiting viral replication, modulating immune responses, and reducing inflammation. It exerts its antiviral and antioxidant effects by activating the Nrf2 pathway and inhibiting multiple inflammation-related signaling pathways, such as TLR4, p38/JNK, and NF-κB. Therefore, Emodin, as a novel candidate for anti-IAV drugs, warrants further in-depth research to evaluate its feasibility and safety for clinical applications.

Resveratrol

Resveratrol, an antioxidant phytoalexin found in red grapes, has chemopreventive and therapeutic effects on various diseases [105]. Resveratrol significantly affects the persistent airway inflammation and airway hyperresponsiveness (AHR) induced by RSV infection. Mice infected with RSV are euthanized at consecutive time points post-infection to collect samples and measure the number of inflammatory cells and levels of interferon-gamma (IFN-γ), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). The administration of resveratrol is followed by assessments of airway inflammation, AHR, as well as NGF and BDNF levels. Additionally, anti-NGF antibodies (Ab-NGF) are used to investigate the role of NGF in the persistent airway inflammation and AHR induced by RSV. The study found that RSV RNA could still be detected in the lungs of RSV-infected mice on day 60, accompanied by persistent airway inflammation and AHR lasting 60 days. Levels of IFN-γ in the bronchoalveolar lavage fluid (BALF) increased on day 7 post-RSV infection but returned to normal levels by day 14 post-infection, while levels of NGF and BDNF gradually increased from day 14 to day 60. Furthermore, treatment with resveratrol led to a reduction in the total cell count in the BALF; the number of inflammatory cells infiltrating the lungs was also lower. Resveratrol attenuated the airway response to acetyl-methacholine and significantly lowered NGF levels in the BALF without affecting BDNF levels. Additionally, administration of Ab-NGF after RSV infection diminished the associated persistent airway inflammation and AHR. Resveratrol inhibits persistent airway inflammation and AHR, potentially in part by reducing NGF levels post-RSV infection [106]. Resveratrol demonstrates significant potential in combating the persistent airway inflammation and AHR caused by RSV infection, particularly by reducing NGF levels to exert its anti-inflammatory and immunomodulatory effects.

Geniposide

Geniposide is an effective iridoid glycoside extracted from Forsythia suspensa predominantly found in the roots, stems, leaves, and fruits of the plant [107]. In terms of medicinal applications, geniposide exhibits pharmacological effects such as anti-inflammatory, weight loss, and anti-tumor activities in vitro and in animal models [108]. Previous studies have found that geniposide inhibits cigarette smoke-induced lung inflammation by activating Nrf2 and inhibiting NF-κB [109]. Similarly, geniposide can alleviate LPS-induced lung inflammation in acute lung injury mice by inhibiting the activation of MAPK and NF-κB [110]. Geniposide A can inhibit M1 expression but does not affect NP expression. This compound blocks the nuclear export of some influenza virus gene mRNAs at the post-transcriptional level, leading to differential production of viral proteins. Another possible mechanism for the reduction in M1 levels is enhanced protein degradation. Cyclophilin A, a member of the cyclophilin family and a peptidyl-prolyl isomerase, has been shown to accelerate the degradation of M1 protein via a ubiquitin/proteasome-dependent pathway, thereby inhibiting influenza virus replication [111]. In vitro studies have shown that, compared to the viral group, the expression levels of NF-κB p65, p-NF-κB p65 proteins were significantly reduced, and the expression levels of p-IκBα were significantly decreased, while the expression levels of IκBα were significantly increased in Huh-7 cells treated with KD-1 (250, 125, 62.5 μg/ml) [112]. This suggests that geniposide A has potential therapeutic effects in inhibiting influenza virus replication. Geniposide demonstrates extensive potential in anti-inflammatory and anti-influenza virus applications. It reduces inflammatory responses by activating the Nrf2 pathway and inhibiting the NF-κB pathway, and it suppresses influenza virus replication by blocking the nuclear export of viral mRNAs and promoting the degradation of the M1 protein.

Glycyrrhizic acid

Glycyrrhizin, also known as glycyrrhizic acid or licorice sweetening glycoside, is a triterpenoid saponin mainly isolated from the roots of the Glycyrrhiza glabra plant [113]. There are several proposed antiviral mechanisms for glycyrrhizin: increasing nitric oxide production in macrophages, affecting transcription factors and cellular signaling pathways, directly altering the viral lipid bilayer, and binding to the ACE2 receptor [114]. Glycyrrhizin influences cellular signaling pathways such as protein kinase C and casein kinase II, as well as transcription factors like activator protein 1 and nuclear factor kappa B. Additionally, glycyrrhizin and its metabolite 18β-glycyrrhetinic acid upregulate the expression of inducible nitric oxide synthase and nitric oxide production in macrophages. Preliminary results indicate that glycyrrhizin induces nitric oxide synthase in Vero cells, and when a nitric oxide donor (BETA NONOate) is added to the culture medium, viral replication is inhibited [115]. This suggests that glycyrrhizin has potential applications in antiviral treatments. Glycyrrhizin is considered a potential therapeutic agent for the novel coronavirus (COVID-19) [116]. In the context of SARS, oral doses of up to 300 mg and intravenous doses of approximately 240 mg have been recommended [117, 118]. Furthermore, research has found that glycyrrhizin can alleviate acute lung injury by inhibiting the HMGB1/TLR4 signaling pathway [119]. Glycyrrhizin demonstrates extensive potential in antiviral and anti-inflammatory applications, particularly in inhibiting viral replication, modulating immune responses, and reducing lung inflammation. Therefore, glycyrrhizin, as a novel antiviral drug candidate, warrants further research to evaluate its feasibility and safety for clinical applications.

Baicalein

Scutellaria baicalensis is a traditional Chinese medicine used for treating common colds, fevers, and influenza virus infections [120, 121]. Flavonoids baicalein and baicalin have demonstrated potent antiviral activity against SARS-CoV-2 in vitro [122]. Research has shown that baicalin can alleviate LPS-induced pulmonary inflammation via the NF-κB and MAPK pathways [123]. In vitro experiments have indicated that baicalin has a half-maximal effective concentration (EC50) of 43.3 μg/ml against influenza virus A/FM1/1/47 (H1N1) and a half-maximal inhibitory concentration (IC50) of 104.9 μg/ml against influenza virus A/Beijing/32/92 (H3N2). When added to MDCK cell cultures post-inoculation with influenza virus, the antiviral activity of baicalin was significantly increased in a dose-dependent manner, indicating that baicalin affects viral budding. Baicalin also exhibits a marked inhibitory effect on neuraminidase, with an IC50 of 52.3 μg/ml against influenza virus A/FM1/1/47 (H1N1) and an IC50 of 85.8 μg/ml against influenza virus A/Beijing/32/92 (H3N2). In vivo studies have shown that intravenous administration of baicalin can effectively reduce the mortality rate of mice infected with influenza A viruses, extend the mean death day (MDD), and improve lung parameters. These results suggest that baicalin acts as a neuraminidase inhibitor with significant inhibitory activity, effectively combating different strains of influenza A viruses in both cell culture and mouse models, indicating potential utility in the management of influenza virus infections [124]. Scutellaria baicalensis and its active component baicalin demonstrate extensive potential in antiviral and anti-inflammatory applications, particularly in inhibiting viral replication, modulating immune responses, and reducing lung inflammation. Therefore, baicalin, as a novel candidate for anti-influenza virus drugs, warrants further research to evaluate its feasibility and safety for clinical applications.

Natural components are gradually gaining attention in the treatment of viral pneumonia due to their diverse biological activities. These components not only potentially have direct antiviral effects but can also enhance the body’s immune response, reduce inflammation, and protect tissues from damage, providing additional protection for patients. Although natural components cannot completely replace traditional antiviral drugs, their role in comprehensive treatment regimens is becoming increasingly important. Traditional antiviral drugs face challenges such as increased drug resistance, more toxic side effects, and limited efficacy against certain types of viruses. The multi-target intervention approach provided by natural components can serve as a complementary therapy, reducing the limitations of using single drugs. Moreover, natural components typically have lower toxicity and fewer adverse reactions, making them safer for long-term use.

To better utilize natural components in combating viral pneumonia, future research should emphasize a deeper understanding of how these components affect viral replication, host immune responses, and inflammatory regulation. Large-scale clinical trials should be conducted to evaluate their safety and effectiveness, ensuring reliability and consistency in human applications. It is also crucial to develop combined treatment strategies that integrate natural components with existing antiviral medications to maximize synergistic effects and improve therapeutic outcomes. Additionally, applying the concept of precision medicine to explore personalized treatment plans for different types of viral pneumonia, tailoring the most suitable methods based on individual patient characteristics, can further enhance treatment efficacy. Through interdisciplinary collaboration and continuous effort, we aim to find safer, more effective, and sustainable solutions to address the global public health challenges posed by viral pneumonia.