TABLE 3.
Potential targets, clinical research, and mechanism of promising anti‐SARS‐COV‐2 natural active products
| Name | Effects | Research progress | Drug dosage regimen | System for experiment | Reference |
| Baicalin/Baicalein (targets:3CLpro & ACE2) | 1.Targeted binds with ACE2. | Preclinical study | None | (silico virtual screen) | (Shakhsi‐Niaei, Soureshjani, & Babaheydari, 2021 ) |
| 2.Targeted inhibits SARS‐COV‐2 3CLpro with IC50 of 1.69 and 10.27 μM respectively. | Preclinical study (in vitro) | Different concentrations of baicalin or baicalein were used to treat COVID‐19 in Vero cells for 48 h | SARS‐COV‐2 in Vero E6 cells | (Su et al., 2020a) | |
| 3. Inhibits 3CLpro in vitro (IC50: 0.39 μM), and in Vero cells (EC50: 2.9 μM). | Preclinical study (in vitro) | Vero cells were pretreated with baicalein for 1 h and then infected with virus for 2 h. The cells were treated with baicalein medium. | SARS‐COV‐2 in Vero E6 cells | (Liu et al., 2021) | |
| 4. SWHD showed better anti influenza virus activity than oseltamivir. | Preclinical study (in vivo) | Use 50 μ L virus suspension containing 10LD50 virus (mice) was inoculated intranasally. Two hours later, the inoculated mice received different concentrations of SWHD extract (5.85, 11.70, or 23.40 g/kg/day) by gavage every day for 5 days. | 10LD50 virus in female BALB/c mice | (Ma et al., 2018) | |
| 5.Improves the inflammatory reaction and lung injury caused by COVID‐19 | Clinical study (RCT) | 235 patients were divided into 4 groups. The experimental group received high (60 ml), medium (40 ml), and low (20 ml) doses of SHL three times a day (in addition to standard treatment). The control group received standard treatment. | COVID‐19 patients | (Ni et al., 2021) | |
| 6.Inhibits inflammatory response, improves immune function and lung function | Clinical study (RCT) | 124 patients with mycoplasma pneumonia were divided into two groups. The control group took azithromycin (once/day, 10 mg/kg/per) and montelukast sodium tablets (once/day, 5 mg per), and the observation group added Shuanghuanglian (3 times/day, 5 g per), 30 days for treatment. | Patients with mycoplasma pneumonia | (Yang, Wang, & Li, 2020) | |
| Keampferol (targets: 3CLpro & ACE2) | 1.Targeted inhibits ACE2 and SARS‐COV‐2 3CLpro | Preclinical study | None | Molecular docking | (Zong, Ding, Jia, Ma, & Ju, 2020) |
| Quercetin (3CLpro and ACE2) | 1.Targeted inhibits ACE2 | Preclinical study | None | Molecular docking | (Shen & Yin, 2021) |
| 2.Targeted inhibits SARS‐COV‐2 3CLpro | Preclinical study | None | Molecular docking | (Zong, Ding, Jia, Ma, & Ju, 2020) | |
| 3.Reduces frequency and length of hospitalization, and invasive oxygen therapy rate | Clinical study (RCT) | Based on the SC (standard of care), the observation group (152 COVID‐19 patients) were given a daily dose of 1,000 mg of QP (quercetin Phy‐tosome ©). For 30 days. | COVID‐19 patients | (Di Pierro et al., 2021). | |
| 4.Reduces EMS, pain and inflammatory factor hs‐TNF α levels in plasma. | Clinical study (RCT plus DB) | 50 female patients were randomized to the quercetin(500 mg/day) or placebo groups for 8 weeks | Women with rheumatoid arthritis | (Javadi et al., 2017) | |
| 5. Quercetin reduces the degree of upper respiratory tract infection. | Clinical study (RCT plus DB) | 1,002 patients with upper respiratory tract infection were divided into 3 groups, respectively received quercetin 500 mg/day, 1,000 mg/day and placebo | Patients with upper respiratory tract infection | (Heinz, Henson, Austin, Jin, & Nieman, 2010). | |
| Rutin (3CLpro and ACE2) | 1.Targeted inhibits ACE2 and SARS‐COV‐2 3CLpro | Preclinical study | None | Molecular docking | (Wu et al., 2021) |
| 2. Decreases MPO level | Clinical study (DB) | Group 1 ate 16.5 mg rutin equivalent/day, group 2 ate 359.7 mg rutin equivalent/day, for 2 weeks. Then change the type of biscuit, they ate for another 2 weeks | Healthy women | (Wieslander et al., 2011) | |
| 3. Improves patients' neurological and inflammatory status (ox‐LDL, NF‐κB p65, TNF‐α and IL‐6) | Clinical study (RCT) | 150 patients with ACI were divided into two groups. Both were given routine treatment. Group 1 were treated with Ginkgo Dharma injection, and patients in the combined treatment group were treated with Ginkgo Dharma injection combined with troxerutin. | ACI (acute cerebral infarction) patients | (Feng, Liu, & Qin, 2021) | |
| Β‐sitosterol (3CL pro) | Targeted binding 3CL pro | Preclinical study | None | Mocular docking | (Narkhede, Pise, Cheke, & Shinde, 2020) |
| Berberine (3CL pro) | 1.Targeted inhibits 3CL pro | Preclinical study | None | Mocular docking | (Liu & Wang, 2020). |
| 2.Decreased interleukins and other inflammatory factors. | Clinical study | 130 ACS patients(received PCI) were divided into two groups. The control group received standard treatment, and 61 patients in the experimental group received erberine treatment(300 similar to mg, t.i.d., for 30 similar to days. | ACS patients | (Meng et al., 2012) | |
| Betulinic acid (3CL pro) | 1.Targeted inhibits 3CL pro (IC50: 5 μM) | Preclinical study | None | Spectrophot‐ometric assay | (Liu & Wang, 2020) |
| 2.Activates the immune response byIncrease the improving CD4+/CD8 + . | Preclinical study (animal trial) | For non‐immunized and red blood cell (SRBC) immunized mice, betulinic acid (50,5,0.5 mg/kg) was orally administered five times every 24 h | SRBC immunized mice | (Jine, Lis, Szczypka, & Obminska‐Mrukowicz, 2012) | |
| Indirubin (3CL pro) | 1.Reduce the expression level of the proinflammatory factor IL‐1β, IL‐6, and TNF‐αmRNA | Preclinical study | 50 μl 0.2 mg/ml LPS was injected into the breast tube and 0.2 ml/20 g 10:1 diluted 25, 50, or 100 μM indirubin were injected by IP at 1 and 12 h. Culture for 24 h | LPS induced mastitis mouse model | (Lai et al., 2017) |
| 2.Targeted binding 3CL pro | Preclinical study | None | Mocular docking | (Narkhede, Pise, Cheke, & Shinde, 2020) | |
| Cordycepin RdRp and 3CLpro | 1.Targeted inhibiting RdRp and 3CL pro (EC50: 2 μ M) | Preclinical study (in vitro) | After Vero E6 was infected with SARS‐COV‐2, cordycepin was administered for 36–48 h (SI > 49.75; EC 50 = 2.0) | (Rabie, 2022) | |
| Curcumin (RdRp/Furin and ACE2) | 1.Targeted inhibiting RdRp protein | Preclinical study | None | Mocular docking | (Singh, Bhardwaj, & Purohit, 2021) |
| 2.Targeted inhibiting Furin and ACE2 protein | Preclinical study | None | Mocular docking | (Verma et al., 2021) | |
| Myricetin NSP15 | Targeted inhibiting NSP15 | Preclinical study | None | Mocular docking | (Sharma et al., 2021) |
| Glycyrrhizin (targets: ACE2& S spike protein) | 1. Inhibits SARS‐COV‐2 infection (EC50: 2.39 μm) | Preclinical study (in vitro) | Vero E6 cells were infected with SARS‐CoV‐2 at 100 μl median tissue culture infectious dose (TCID50), in the presence of glycyrrhizin. | Vero E6 cells infected by SARS‐CoV‐2 | (Zhu et al., 2020) |
| 2.Targeted inhibits ACE2 | Preclinical study | None | Mocular docking | (Ahmad, Waheed, Abro, Abbasi, & Ismail, 2021) | |
| 3.Targeted inhibits Spike protein | Preclinical study | None | Mocular docking | (Li et al., 2021) | |
| 4.Regulates the ex‐pression of HMGB1, NF‐κB, COX‐2, ILS, TNF and other factors | Preclinical study (in vivo) | Glycyrrhizin (2, 4, and 10 mg/kg) was administered by intra‐articular injection for 12 weeks | Male Wistar rats | (Luo et al., 2021) | |
| 5.GF‐ β 1, TNF‐α, liver function and fibrosis were significantly improved | Clinical study | All patients took adefovir dipivoxil orally (10 mg/time, once/day). Study groups were added with compound glycyrrhizin injection (intravenous drip, once/day). Treat for 12 months. | Hepatitis B patients | (WANG, LUO, & CHEN, 2018) | |
| 6.TNF‐α, IL‐6 level of the inflammatory factor in chronic hepatitis B patients were decreased | Clinical study | All patients receive compound glycyrrhizin injection (20 mL/branch, intravenous drip ~2 h), treatment was 2–4 weeks | Hepatitis B patients | (Fang & Shuan‐lin, 2009) (Cai, Zhang, & Zhang, 2004) | |
| 7. Improves chest tightness, cough and pain, protects liver function index | Clinical study | 102 patients with SARS were divided into the control group and the observation group. 27 cases of observation group were treated with compound glycyrrhizin (160 mg·d‐1). | Patients with SARS | ||
| 8. The serum ALT and AST of mild and severe patients tended to return to normal levels after DG treatment | Clinical study | 59 SARS‐COV‐2 patients receive diammonium glycyrrhizinate treatment. | Patients with SARS‐COV‐2 | (Liao et al., 2021) | |
| Nicotinamine (targets: ACE2) | 1.Targeted inhibits ACE2 activity | Preclinical study | None | LC–MS | (Takahashi, Yoshiya, Yoshizawa‐Kumagaye, & Sugiyama, 2015) |
| Chlorogenic acid (targets: ACE2) | Targeted inhibits ACE2 | Preclinical study | None | Mocular docking | (Yu, Wang, & Bao, 2020) |
| Honokiol (targets: Furin) | Targeted inhibits furin protein and SARS‐COV‐2 infection(25 μ M (99.83%) and 50 μ M (99.96%)) | Preclinical study (in vitro) | Vero E6/TMPRSS2 cells were infected with SARS‐COV‐2 (WK‐521) in the presence of honokiol (100, 50, 25, 12.5, 6.25, and 和 3.125 μM) for 24 h | Vero E6/TMPRSS2 cells infected with SARS‐COV‐2 | (Tanikawa, Hayashi, Suzuki, Kitamura, & Inoue, 2021) |
Abbreviations: DB, double blind; RCT, randomized controlled trial.