Antiviral mechanisms of candidate chemical medicines and traditional Chinese medicines for SARS-CoV-2 infection

2.1. Host protein targeted medicines

Chloroquine (CQ) and its derivatives, especially hydroxychloroquine (HCQ) and chloroquine phosphate, are widely-used anti-malarial and autoimmune disease drugs, which can be distributed throughout the whole body after oral administration (Chang and Sun, 2020; Devaux et al., 2020; Gao et al., 2020a; Kearney, 2020; Li and Liu, 2020; multicenter collaboration group of Department of, S., Technology of Guangdong, P., Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus, p., 2020; Wang et al., 2020d). In recent years, CQ is proved to be a broad-acting antiviral effective agent against numerous viruses, including Influenza viruses, Human immunodeficiency virus (HIV), Hand-Foot-and-Mouth Disease (HFMD), Kaposi's sarcoma-associated herpesvirus (KSHV), Chikungunya virus (CHIKV), hepatitis B virus (HBV) and other inflammation-related viruses (Devaux et al., 2020; Khan et al., 2010; Tan et al., 2018; Yang et al., 2016). CQ and its derivatives can increase the pH value of endosome, interfere with glycosylation of cellular receptors, inhibit autophagosome-lysosome fusion, interfere signal pathways, disturb the post-translational modification of viral proteins, modulate the immune responses, and reduce inflammatory reactions (Chang and Sun, 2020; Devaux et al., 2020; Kearney, 2020; Khan et al., 2010; Sinha and Balayla, 2020; Wang et al., 2020a; Yang et al., 2016), and thus blocking the early and late stages of the virus infection. Furthermore, CQ and HCQ can prevent the ORF1ab, ORF3a, and ORF10 of SARS-CoV-2 from attacking heme to form porphyrin, and inhibit the viral ORF8 and surface glycoprotein from binding to porphyrin, thus effectively relieving respiratory distress symptoms (Liu and Li, 2020). Because of its immunomodulatory activities, CQ and its derivatives were also used to control cytokine storms in critical patients with SARS-CoV-2 infection in the late stage (Zhou et al., 2020a). Moreover, hydroxychloroquine is safer and more effective than CQ at inhibiting SARS-CoV-2 in vitro and in vivo (Gautret et al., 2020; Liu et al., 2020b; Yao et al., 2020b; Zhou et al., 2020a). Therefore, it was recommended to use 400 mg of hydroxychloroquine sulfate twice daily for 1 day, followed by 200 mg twice daily for 4 more days for the treatment (Yao et al., 2020b). Furthermore, a combination of hydroxychloroquine sulfate (200 mg, three times per day during ten days) and azithromycin (500 mg on day1 followed by 250 mg per day, the next four days) can significantly reduce the viral load compared with that of the hydroxychloroquine treatment alone (Gautret et al., 2020). Taken together, the CQ and its derivatives can shorten the course of SARS-CoV-2, reduce the inflammatory responses to infection, inhibit the deterioration of pneumonia, improve lung imaging performance, and promote the negative conversion of the virus (Kearney, 2020; Li and Liu, 2020). However, recent reports show that treatment with HCQ is associated with numerous adverse effects in patients with COVID-19, such as frequent QTc prolongation, erythema multiforme, acute generalized exanthematous pustulosis (Bessiere et al., 2020; Delaleu et al., 2020; Mercuro et al., 2020; Monte Serrano et al., 2020; Ren et al., 2020b; Torjesen, 2020). On Jun 16, 2020, the US Food and Drug Administration revoked the emergency use authorization for chloroquine and hydroxychloroquine due to their lack of efficacy and safety concerns (http://www.chinadaily.com.cn/). Therefore, the safety assessment of CQ/HCQ and the combination of HCQ and other medicine should be conducted for patients with COVID-19.

Arbidol (ARB, also known as umifenovir) is a broad-spectrum antiviral drug that can inhibit numerous DNA and RNA viruses, including influenza virus, Zika virus, West Nile virus and hepatitis C virus (Blaising et al., 2014; Haviernik et al., 2018). It was reported that ARB can interact with both cellular membranes and viral and/or cellular proteins, and thus preventing membrane fusion, blocking trimerization of the spike glycoprotein and virus infection (Blaising et al., 2014; Vankadari, 2020). ARB also has immunostimulating effects, such as stimulating the production of interferon, activating the humoral and cellular immune defense of the body, enhancing the phagocytic activity of macrophages (Blaising et al., 2014; Haviernik et al., 2018). Moreover, ARB exhibits a prolonged antioxidant capacity by reacting with free radicals in two stages (Proskurnina et al., 2020). Therefore, it was supposed that ARB can inhibit SARS-CoV-2 infection at several stages, which is currently used in several clinical trials for the COVID-19 treatment. Furthermore, it was reported that ARB combined with Lopinavir/Ritonavir (LPV/r) is better than LPV/r alone in the treatment of the COVID-19 (Deng et al., 2020). ARB/IFN-α2b Therapy and ARB/adjuvant therapy are helpful to relieve COVID-19 pneumonia (Chen et al., 2020b; Xu et al., 2020b). However, another group found that arbidol monotherapy has little effect on improving clinical outcomes of mild/moderate patients (Li et al., 2020d). These results demonstrate that a combination of different compounds with ARB targeting different stages of the viral infection might be a promising stream in the antiviral treatment of the COVID-19. Notably, it is not recommended to use three or more antiviral drugs simultaneously (PRC, 2020).

Apart from CQ and ARB recommended by WHO and NHC of China, some compounds also exhibit promising characteristics in the treatment of the COVID-19. The first one is teicoplanin, which is a commonly used glycopeptide antibiotic in the treatment of Gram-positive bacterial infection, especially in staphylococcal and streptococcus infections (Baron et al., 2020; Ren et al., 2020c). Recently, it was reported that the antibiotic can be used against various viruses such as Ebola, influenza virus, flavivirus, hepatitis C virus, HIV, Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV (Colson and Raoult, 2016; Zhou et al., 2016). Teicoplanin can inhibit entry of the pseudoviruses (HIV-luc/2019-nCoV-S) by specifically blocking the activity of host cysteine proteases cathepsin L in the late endosomes, and thus inhibiting the release of genomic viral RNA and the virus replication cycle (Baron et al., 2020; Ren et al., 2020c). Therefore, the half-maximal (50 %) inhibitory concentration (IC₅₀) of teicoplanin is 1.66 u M on the pseudoviruses, and the recommended usage is 400−1200 mg/day intravenously or orally (Baron et al., 2020; Ren et al., 2020c)(Ceccarelli et al., 2020).

Another compound is niclosamide, which is an FDA-approved anthelminthic drug against tapeworm infections for several decades (Xu et al., 2020a). It is a multifunctional drug that can inhibit oxidative phosphorylation and stimulate adenosine triphosphatase activity in the mitochondria, regulate multiple signaling pathways and biological processes, including Wnt/β-catenin, mTORC1, STAT3, NF-κB, Notch, NS2B-NS3 interaction, and pH (Kratky and Vinsova, 2011; Pindiprolu and Pindiprolu, 2020; Xu et al., 2020a). These results suggest that niclosamide has broad-spectrum antiviral activities. Furthermore, the derivatives of niclosamide, such as 2-chloro-4-nitroanilide, O-alkylamino-tethered, or salicylamide derivatives, also exhibit more potent and orally bioavailable for antiviral treatments (Kratky and Vinsova, 2011; Xu et al., 2020a). Moreover, niclosamide may inhibit endocytosis of SARS-CoV-2 by blocking ACE2, and prevent autophagy of SARS-CoV-2 by inhibiting of S-Phase kinase-associated protein 2 (Pindiprolu and Pindiprolu, 2020). However, the antiviral activities of niclosamide and its derivatives in SARS-CoV-2 infection need further research and clinical verification.

3.1. For medical observation

For medical observation of COVID-19, several prescriptions can be used clinically, including Huoxiang Zhengqi capsules (pills, liquid, or oral solution), Jinhua Qinggan granules/capsules, Lianhua Qingwen capsules/granules, Shufeng Jiedu capsules/granules, Fangfeng Tongsheng pills/granules, and Yupingfeng San (Jin et al., 2020; Liu et al., 2020e; PRC, 2020; Xu and Zhang, 2020).

Huoxiang Zhengqi capsules (pills, liquid, or oral solution, HXZQ) consists of 10 Chinese herbs, with 778–2347 chemical ingredients (Jiang et al., 2020). Among these ingredients, more than 13 ingredients, including protocatechuic acid, chlorogenic acid, caffeic acid, liquiritin, hesperidin, apigetrin, rosmarinic acid, oxypeucedanin hydrate, byakangelicin, apigenin, glycyrrhizin, nobiletin, and 6-gingerol, are recognized as critical chemical marker compounds (Kim et al., 2014). HXZQ is widely used to dissipate cold and eliminate dampness targeting on the clinical features of fatigue and gastrointestinal discomfort (Jin et al., 2020; PRC, 2020). Moreover, this prescription is also used in the treatment of clinical symptoms as hypodynamia accompanied by gastrointestinal upset, as well as the exterior syndrome of cold-dampness (Jin et al., 2020; PRC, 2020). It was reported that HXZQ can regulate the immune response of CD4⁺ and CD8⁺ cells and suppress the levels of TNF-α in the intestine (He et al., 2006; Tong et al., 2020). Results of molecular docking showed that PTGS2, HSP90AB1, CAMSAP2, mPGES-1, LTA4H, NOS2 are possible targets of HXZQ in COVID-19 (Huang et al., 2020; Tong et al., 2020). Therefore, HXZQ has anti-inflammatory and immunomodulatory effects in COVID-19 by inhibiting inflammatory factors and regulating immune response (Huang et al., 2020; Tong et al., 2020).

Lianhua Qingwen capsules/granules, Shufeng Jiedu capsules/granules, Fangfeng Tongsheng pills/granules, Jinhua Qinggan granules/capsules, and Yupingfeng San are commonly used to against influenza virus infection (Jin et al., 2020; PRC, 2020; Xu and Zhang, 2020). For example, Lianhua Qingwen capsules/granules (LHQW) composed of 13 herbs, with 733–3084 chemical ingredients (Jiang et al., 2020), has broad-spectrum activities against influenza viruses (IAV) (Ding et al., 2017) as well as other respiratory diseases, such as chronic rhinosinusitis (Lin et al., 2020a), chronic obstructive pulmonary disease (Dong et al., 2014), etc. LHQW can block the early stage of virus infection, impair the nuclear export of the viral RNP, and modulate immune responses during virus infection (Ding et al., 2017). LHQW also can inhibit the replication of SARS -CoV-2, affect virus morphology, improve human immunity, and decrease inflammatory response or even cytokine storm (Hu et al., 2020; Li et al., 2020c; Tong et al., 2020; Ye et al., 2020). Meanwhile, three components of LHQW, Rutin, Forsythoside E, and Hyperoside, can bind the protease of SARS-CoV-2, with the binding energy of −9.1, −9.0 and −8.7 kcal/mol, respectively, forming hydrogen bonds and hydrophobic interactions between the active components and the viral protease (Ye et al., 2020). Moreover, chemical components of LHQW may also target cellular JAK-STAT, EGFR, ACE2, MAPK, PI3K-AKT, and NF-κB, etc (Huang et al., 2020; Tong et al., 2020). These results demonstrate that LHQW seems an effective TCM against SARS-CoV-2 infection.

Shufeng Jiedu Capsule/Granule (SFJD), consisting of eight medicinal herbs, is a widely used TCM for its antiviral, antibacterial, antitumor, and anti-inflammatory activities (Mei et al., 2020). It was reported that SFJD may protect lung injury and neuronal loss by enhancing autophagy and reducing apoptosis in rats with allergic rhinitis (Mei et al., 2020). It improves upper respiratory tract infection induced by Pseudomonas aeruginosa through various targets, especially ERK phosphorylation (Li et al., 2017). SFJD effectively regulates anti-inflammatory and immunoregulatory activities during acute lung injury through AKT1 regulation (Tao et al., 2017). Besides, SFJD combined with oseltamivir treatment significantly reduced IAV-induced airway inflammation and pulmonary virus titer (Ji et al., 2020). These results suggest SFJD may prevent and cure diseases, especially infectious diseases, by regulating various signal pathways.

3.2. For mild infection

For mild infection of SARS-CoV-2, Qingfei Paidu Decoction (QFPD), Sangju yin, and Yinqiao san were suggested to use in clinical (Jin et al., 2020; PRC, 2020; Xu and Zhang, 2020). Additionally, QFPD, Huashi Baidu Recipe, and Xuanfei Baidu Recipe are three new prescriptions specifically designed for the COVID-19, which exhibit active and effective roles in the prevention and treatment of the disease.

QFPD has more than 300 active ingredients and can act on more than 790 targets. QFPD might inhibit the invasion and replication of SARS-CoV-2 by directly targeting the viral 3C protein and host ACE2 (Huang et al., 2020). Recent studies showed that QFPD can improve several pathways in patients with COVID-19, such as response to oxygen levels, response to oxidative stress, and blood circulation (Wang et al., 2020e). Moreover, QFPD also can inhibit arachidonic acid metabolic pathway, and thereby regulating inflammatory cytokines (Ren et al., 2020c), suggesting this decoction has a positive effect on COVID-19 treatment. However, the exact biological mechanisms and side effects of these prescriptions need to be further evaluated.

Moreover, Xuanfei Baidu Recipe (XFBD) consists of 13 herbs, which acts on lung meridian by balancing immunity, eliminating inflammation, regulating hepatic and biliary metabolism, and recovering energy metabolism balance (Wang et al., 2020f).

This work was financially supported by the Changchun Science and Technology Bureau emergency project [No.2020RW002]; the National Key Research and Development Program of China [No. 2017YFD0500103]; the National Natural Science Foundation of China [No. 31772747]; the Jilin Province Science and Technology Development Projects [No. 20200402043NC]; and the Science and Technology Research Program during the 13th Five-Year Plan Period of Jilin Educational Committee [No. JJKH20190172KJ]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.