Chinese Herbal Medicines As a Source of Molecules with Anti-Enterovirus

Wang et al. Chin Med (2016) 11:2 DOI 10.1186/s13020-016-0074-0 Chinese Medicine REVIEW Open Access Chinese herbal medicines as a source of molecules with anti‑enterovirus 71 activity Mengjie Wang1,2, Ling Tao1,2,3 and Hongxi Xu1,2* Abstract Enterovirus 71 (EV71) is one of the causative agents of hand, foot, and mouth disease (HFMD), which sometimes leads to severe neurological disease and death in the Asia–Pacific region. In Chinese medicine, HFMD is caused mainly by an accumulation of damp-heat and toxicity in the body. No effective drugs are currently available for the treatment and prevention of EV71 infection. This review summarizes the potential Chinese herbal extracts and isolated compounds with antiviral activity against EV71 and their clinical applications, especially those categorized as heat-clearing and detoxifying. Background with considerable side effects in infants and children Enterovirus 71 (EV71) is a non-enveloped, positive-sense, [10, 11]. Pleconaril, an antipicornavirus capsid-binding single-stranded RNA virus that is 7.4 kb in length and agent, shows moderate efficacy in anti-EV71 treatment, belongs to the family Picornaviridae [1]. Infection with but cannot reduce the cytopathic effect (CPE) induced EV71 commonly causes mild hand, foot, and mouth dis- by some EV71 strains [12, 13]. Rupintrivir, an inhibitor of ease (HFMD), which sometimes leads to serious neuro- human rhinovirus (HRV) 3C protease, specifically binds logical complications such as aseptic meningitis, brain to the 3C protease of EV71, inhibits the replication of stem encephalitis, pulmonary edema, and poliomyelitis- EV71 in vitro, and strongly contains the spread of EV71 like paralysis, and eventually causes death especially in infection in vivo [14]. However, this drug has not yet infants and children [2]. The potential fatal implications been used for clinical treatment of EV71 infection. pose a great threat to infants and children under 5 years In addition to synthetic compound design, Chinese of age [3]. Since the first isolation of EV71 in the United herbal medicines (CHMs) contain a wide range of phyto- States in 1969, there have been several outbreaks of EV71 chemicals and comprise a potential source of anti-EV71 in Bulgaria, Malaysia, Taiwan, and China that caused active agents [15]. According to Chinese medicine (CM) considerable levels of infection and mortality [4–7]. theory, diseases occur and develop through the effects However, neither a precautionary vaccine nor a specific of pathogenic factors on the human body that lead to an antiviral drug is available for the treatment of EV71 infec- imbalance of qi, xue, yin, and yang, or organs and merid- tion [6]. ians in the body [16]. Herbs have different impacts on Interferons (IFNs) are a group of antiviral proteins the human body to regulate qi, xue, yin, and yang, and (mainly glycoproteins) that regulate host cytokines and balance the whole body. HFMD is caused mainly by an chemokines [8]. Infection with EV71 attenuates the IFN accumulation of damp-heat and toxicity in the body, and response, and reduces the antiviral effect of IFNs [9]. therefore its treatment may involve the usage of heat- Although ribavirin, a nucleoside analog, has been clini- clearing and detoxifying medicines. In this review, stud- cally used as a broad-spectrum antiviral drug, treatment ies on CHM extracts and compounds with anti-EV71 of EV71 infection by ribavirin has been unsatisfactory activity are summarized, based on CHMs categorized into heat-clearing and detoxifying medicines. Future per- *Correspondence: [email protected] spectives and challenges in anti-EV71 drug development 1 School of Pharmacy, Shanghai University of Traditional Chinese involving herbal medicines are also discussed. Medicine, Shanghai 201203, China Full list of author information is available at the end of the article © 2016 Wang et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Chin Med (2016) 11:2 Page 2 of 26 Extracts with anti‑EV71 activity leaves exerted antiviral effects against EV71 and CVA16 Extracts of CHMs have shown significant antiviral effects with EC50 values of 35.88 and 42.91 µg/mL, respectively against EV71 with low EC50 values and high selective [36]. The extract inhibited virus-induced apoptosis, inac- index (SI) values. Previous studies, formulae, and clini- tivated viral 2A protease, and reduced the expression of cal experiences with CHMs and ethnomedicines revealed IL-6 and RANTES. The extract also reduced the virus inhibitory effects on a range of viruses, such as influenza yield in the intestine of EV71-infected suckling mice. The virus, hepatitis B virus (HBV), dengue virus, and cox- ethyl acetate (EA) fraction of the extract showed greater sackie virus B3 (CVB3) [17–20]. Extracts of CHMs may antiviral activity than the n-butanol or aqueous frac- be complementary to modern medicines. Extracts with tions, exhibiting EC50 values of 4.21 µg/mL against EV71 anti-EV71 activity are summarized in Table 1. and 9.08 µg/mL against CVA16 [37]. Eupafolin, a major component of the EA fraction, showed EC50 values of Heat‑clearing and detoxifying medicines 1.39 µM against EV71 and 5.24 µM against CVA16. Eupa- Heat-clearing and detoxifying medicines comprise a vari- folin attenuated the virus-induced upregulation of IL-6 ety of herbal medicines that can be used to treat heat- and RANTES by inhibiting the virus-induced ERK1/2, related syndromes such as high body temperature, thirst AP-1, and STAT3 signals. in the mouth and throat, constipation, inflammation, and Saururus chinensis (Lour.) Baill (San Bai Cao) exhib- pain [21]. ited a variety of bioactivities for the treatment of edema, Houttuynia cordata Thunb. (Yu Xing Cao) eliminated jaundice, cancer, and inflammatory diseases [38]. The heat and toxicity in the human body and promoted uri- water extract of S. chinensis showed significant antiviral nation [22]. The herb exhibited anti-inflammatory, anti- activity against EV71 with an EC50 of 8.9 µg/mL by inhib- cancer, and antiobesity activities, and blocked infection iting the activation of the MEK1/ERK signaling pathway, of herpes simplex virus (HSV) [23–26]. In a screening and rutin was identified as the major component respon- of 22 CHMs, a water extract of H. cordata Thunb. inhib- sible for this activity [36]. ited the CPE and plaque formation induced by EV71 in The bark, leaves, and flowers of Paulownia tomen- Vero cells with an EC50 of 125.92 µg/mL [27]. The H. cor- tosa (Pao Tong) have been applied to the treatment data Thunb. extract (125 µg/mL) lowered the 50 % viral of infections and inflammatory diseases in CM [39]. RNA yield, reduced viral protein 3A expression, and The methanol extract of P. tomentosa flowers dem- inhibited EV71-induced apoptosis in comparison with onstrated anti-EV71 activity with a dose-dependent the untreated group, and among five tested pure com- reduction of the CPE and an EC50 of 65 µg/mL. Further pounds extracted from H. cordata Thunb., chlorogenic bioactivity-guided isolation led to the discovery of the acid showed a moderate anti-EV71 effect with an IC50 of pure anti-EV71 compound apigenin, which inhibited 102.53 µg/mL. The water extract of H. cordata Thunb. viral replication [40]. had anti-EV71 activity against the Fuyang and BrCr The EA and butanol extract of Phyllanthus urinaria strains in Vero cells with EC50 values of 8.9 and 20.6 µg/ (Zhen Zhu Cao) was reported to possess antiviral activity mL, respectively [28]. Incubation of the extract before or against EV71 and CVA16 based on CPE reduction assays, during inoculation significantly suppressed EV71 infec- with corilagin identified as the major active component tion and also inhibited the CPE of coxsackievirus A16 [41]. (CVA16), another causative agent of HFMD. Pre-treatment with the extract prevented EV71-induced IκBα Other medicines degradation and downregulated interleukin (IL)-6 gene Salvia miltiorrhiza (Dan Shen) has been widely used expression. in CM to improve blood circulation, relieve blood sta- Paris polyphylla Smith (Qi Ye Yi Zhi Hua) is used for sis, and treat coronary heart disease [42]. Wu et al. [43] the treatment of snake bites [29]. P. polyphylla Smith pos- obtained seven extracts of S. miltiorrhiza, and two frac- sessed anticancer activity, and saponins from the herb tions derived from water extracts showed anti-EV71 exhibited antifungal effects [30, 31]. The 95 % ethanol activity in CPE inhibition assays with EC50 values of extract of P. polyphylla Smith showed antiviral activity 0.742 mg/mL for fraction SA1 and 0.585 mg/mL for SA2. against four strains of EV71 and CVB3 with EC50 values Both fractions exhibited antiviral activity against three of 78.46–125.00 µg/mL [32]. The extract inhibited both strains of EV71 in Vero, RD, and MRC-5 cell lines. The viral replication and associated increases in IL-6 levels. extracts also inhibited EV71-induced plaque formation Kalanchoe gracilis (KGS) (Deng Long Cao) can be used and apoptosis. to treat injuries, pain, inflammation, and fever because Pueraria lobata (Ge Gen) is commonly used for the of its antioxidative, anti-inflammatory, analgesic, and treatment of cold, fever, and dysentery [44]. P. lobata anticancer activities [33–35]. The water extract of KGS exhibited antidiabetic, anti-inflammatory, antioxidant, Wang Wang et al.

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