Natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.
Chinese herbal medicines and natural compounds possess promising antiviral effects against Human coronaviruses (HCoVs) and provide a rich resource for novel antiviral drug development. This review provides an update on natural compounds against HCoVs and summarizes the active natural compounds and their possible action mechanisms.
Chinese herbal formulae against CoVs
TCM has been used for the treatment of epidemic diseases for a long history and accumulated rich experience. Thus, the antiviral activities are not limited to natural compounds, and also extended to TCM formulae. For example, Lian-Hua-Qing-Wen Capsule (LHQWC, Clearing Pestilential Disease with Forsythiae Fructus-Lonicerae Capsule), a commonly used Chinese medicine preparation, is widely used in clinical practice to treat viral influenza, and plays a very important role in the fight against SARS-CoV58, 59, 60 in particular. LHQWC has been reported to exert inhibitory effects on the SARS-CoVs in cultured Vero-E6 cells, with the EC50 value of 0.11 mg/mL61. LHQWC ameliorated the clinical symptoms such as fever, cough, fatigue and shortness of breath in 63 patients with COVID-1962. A recent study by Academician Nanshan Zhong revealed that LHQWC significantly inhibited the SARS-CoV-2 replication with the IC50 value of 411.2 μg/mL, affected virus morphology, and exerted anti-inflammatory activity in vitro63. They also conducted a prospective multicenter open-label randomized controlled trial on the effectiveness of LHQWC in 284 confirmed cases of COVID-19 (142 each in treatment and control group). The results showed that COVID-19 patients treated with LHQWC for 14 days resulted in a significantly higher recovery rate (91.5% vs. 82.4%, P = 0.022), a markedly shorter median time to symptom recovery (7 vs. 10 days, P < 0.001), as well as a dramatically shorter time to recovery of fever (2 vs. 3 days), fatigue (3 vs. 6 days) and coughing (7 vs. 10 days) (P < 0.001 for all) than the control group (baseline treatment). The results of this trial amply attested the safety and efficacy of LHQWC in patients with COVID-1964. In a retrospective clinical analysis, it was revealed that LHQWC could significantly ameliorate the major symptoms associated with the novel coronavirus-infected pneumonia (NCIP) patients by shortening the duration of fever and cough, and improving the recovery rate65. Moreover, the functional indications of LHQWC have been added to the originally approved indications for COVID-19 treatment. LHQWC can be used to treat clinical symptoms such as fever, cough, and fatigue for the light and common types of COVID-19 patients.
As revealed by network pharmacology approach, Ren-Shen-Bai-Du-San (Ginseng to Defeat Toxicity Powder) may inhibit the cytokine storm formation in COVID-19 patients through regulating chemokines, increasing blood oxygen saturation, inhibiting signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), phosphoinositide 3-kinases (PIK3K) and interleukin-6 (IL-6) signaling pathways67. Another TCM formula, Qing-Fei-Jie-Du Decoction (Decoction for Clearing the Lung and Detoxification) was used for the prevention and treatment of SARS68 and also recommended for COVID-19 treatment according to the 7th edition of the Guidelines of Diagnosis and Treatment for COVID-1969 issued by the National Health Commission of China. Based on this latest edition of the Guidelines, several TCM formulae were recommended for the prevention and treatment of patients with COVID-19, including Jin-Hua-Qing-Gan Granule70,71 (Lonicerae Flos for Clearing Influenza Granule), Huo-Xiang-Zheng-Qi Water (Agastaches Herba Qi-Correcting Water), Shu-Feng-Jie-Du Capsule72, 73, 74 (Wind-Expelling and Detoxification Capsule), Xue-Bi-Jing Injection75 (Blood Definitely Be Cleansed Injection Fluid) and other herbal formulae (as shown in Table 258, 59, 60,62,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81). Among the components of these formulae, Rhei Radix et Rhizoma, Scutellariae Radix, Glycyrrhizae Radix et Rhizoma, Bupleuri Radix, Lonicerae Japonicae Flos, Isatidis Radix and Houttuyniae Herba have been found to exert antimicrobial activities.
Discussion and perspectives
Our present review provides an important update on a number of natural products that have shown promise as anti-CoV agents and potential for COVID-19 treatment. However, since many studies about the antiviral effects of the natural compounds and Chinese medicine in this domain are only preliminary, in-depth in vivo studies on appropriate animal models are needed to unravel the underlying cellular and molecular mechanisms. Pharmacokinetic studies on the promising natural compounds are few and far between, and should be conducted to obtain pharmacokinetic profile, including absorption, distribution, metabolism and excretion parameters. Moreover, clinical trials (phase I to III) are required to test their anti-CoV efficacy and safety on human subjects. More importantly, investigations should be carried out to explore the potential interactions between TCM or natural products and available antivirals on anti-CoV effects. Optimization of some of the aforementioned lead compounds with known or new mechanisms of action may lead to eventual development of new therapeutics for COVID-19.
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