Virus vs Bacteria
Coronavirus (CoV), coxsackievirus (CV), dengue virus (DENV), enterovirus 71 (EV71), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), influenza virus, measles virus (MV) and respiratory syncytial virus (RSV)
Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines. Viruses are responsible for a number of human pathogeneses including cancer. Several hard-to-cure diseases and complex syndromes including Alzheimer's disease, type 1 diabetes, and hepatocellular carcinoma have been associated with viral infections.[1,2,3] Moreover, due to increased global travel and rapid urbanization, epidemic outbreaks caused by emerging and re-emerging viruses represent a critical threat to public health, particularly when preventive vaccines and antiviral therapies are unavailable. Examples include the recent emergence of dengue virus, influenza virus, measles virus, severe acute respiratory syndrome (SARS) virus, and West Nile virus outbreaks.[4,5,6] To date, however, many viruses remain without effective immunization and only few antiviral drugs are licensed for clinical practice. The situation is further exacerbated by the potential development of drug-resistant mutants, especially when using viral enzyme-specific inhibitors, which significantly hampers drug efficacy.[7,8,9,10] Hence, there is an urgent need to discover novel antivirals that are highly efficacious and cost-effective for the management and control of viral infections when vaccines and standard therapies are lacking. Herbal medicines and purified natural products provide a rich resource for novel antiviral drug development. Identification of the antiviral mechanisms from these natural agents has shed light on where they interact with the viral life cycle, such as viral entry, replication, assembly, and release, as well as on the targeting of virus–host-specific interactions. In this brief report, we summarize the antiviral activities from several natural products and herbal medicines against some notable viral pathogens including coronavirus (CoV), coxsackievirus (CV), dengue virus (DENV), enterovirus 71 (EV71), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), influenza virus, measles virus (MV), and respiratory syncytial virus (RSV) [Table 1].
- CORONAVIRUS CoV is an enveloped, positive-sense single-stranded RNA (ssRNA) virus belonging to the Coronaviridae family. The CoV family consists of several species and causes upper respiratory tract and gastrointestinal infections in mammals and birds. In humans, it mainly causes common cold, but complications including pneumonia and SARS can occur. The known human CoV (HCoV) includes HCoV-229E, -OC43, -NL63, -HKU1, and the more widely known severe acute respiratory syndrome coronavirus (SARS-CoV) which caused a global threat with high mortality in 2003. In 2012, the World Health Organization (WHO) designated a sixth type of HCoV infection identified as the Middle East respiratory syndrome coronavirus (MERS-CoV) which is associated with high fatality. There are no specific treatments for CoV infection and preventive vaccines are still being explored. Thus, the situation reflects the need to develop effective antivirals for prophylaxis and treatment of CoV infection. We have previously reported that saikosaponins (A, B2, C, and D), which are naturally occurring triterpene glycosides isolated from medicinal plants such as Bupleurum spp. (柴ﾄ缟ﾓ Ch疂 H, Heteromorpha spp., and Scrophularia scorodonia (玄ｺ參ﾒ Xu疣 Shēn), exert antiviral activity against HCoV-22E9. Upon co-challenge with the virus, these natural compounds effectively prevent the early stage of HCoV-22E9 infection, including viral attachment and penetration. Extracts from Lycoris radiata (石ﾎ筤f Shí Suŕn), Artemisia annua (愽絏ﾔ筁Hu疣g Huā Hāo), Pyrrosia lingua (石ﾎ箚ｯ ShW), and Lindera aggregata (烏G稛Z Wū Yŕo) have also been documented to display anti–SARS-CoV effect from a screening analysis using hundreds of Chinese medicinal herbs. Natural inhibitors against the SARS-CoV enzymes, such as the nsP13 helicase and 3CL protease, have been identified as well and include myricetin, scutellarein, and phenolic compounds from Isatis indigotica (板ﾂ稳根分 Bǎn L疣 Gēn) and Torreya nucifera (榧ﾐ F).[16,17,18] Other anti-CoV natural medicines include the water extract from Houttuynia cordata (撦纛姨粷YXīng Cǎo), which has been observed to exhibit several antiviral mechanisms against SARS-CoV, such as inhibiting the viral 3CL protease and blocking the viral RNA-dependent RNA polymerase activity.
- COXSACKIEVIRUS CV, including subgroups A (CVA) and B (CVB), is a member of the Picornaviridae family, and the non-enveloped positive-sense ssRNA virus is typically transmitted by fecal–oral route and contact with respiratory secretions. While the symptoms of infection can include mild illnesses such as fever, malaise, rashes, and common cold-like presentation, more severe cases may result in diseases of the central nervous system, including aseptic meningitis, encephalitis, and paralysis. CVA is best known as one of the causative agents of hand, foot, and mouth disease (HFMD) in young children. Unfortunately, there is no vaccine or specific antiviral therapy available to prevent CV infection or the diseases it causes. Nevertheless, drugs discovered from natural products, herbs, and traditional decoctions have shown some promise for the development of therapeutics against CV infection. The aqueous extract, ethanolic extract, and bioactive compounds including linalool, apigenin, and ursolic acid from the popular culinary/medicinal herb Ocimum basilicum (sweet basil) (羅勒 Luó Lč) have been observed to possess antiviral activity against CVB1. In particular, ursolic acid interferes with CVB1 replication post-infection. Raoulic acid from Raoulia australis has also been reported as a potential antiviral agent against several CVB subtypes, but the mechanism of its effect is unclear. In addition, we have previously reported that both the medicinal prescription Xiao-Chai-Hu-Tang (小ｬ柴ﾄ缟ﾓ湯Xiǎo Ch疂 HTang) and its major component herb Bupleurum kaoi (柴ﾄ缟ﾓ Ch疂 H inhibit CVB1 infection via the induction of type I interferon response.[23,24] This finding suggests that type I interferon inducers may be helpful in controlling CVB infection and could be further explored as a treatment strategy.
- DENGUE VIRUS DENV is an enveloped positive-sense ssRNA virus of the Flaviviridae family. As a prominent arbovirus in Southeast Asia, DENV is transmitted by mosquito bites, typically by Aedes aegypti. Four serotypes of the virus exist (DENV1 − 4) and all can cause dengue fever. Clinical manifestations of DENV infection can include inapparent/mild febrile presentation, classical dengue fever (fever, headache, myalgias, joint pains, nausea, vomiting, and skin rash), and life-threatening hemorrhagic diseases, specifically dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in severe cases. Despite being an old disease, current immunization and therapeutic options available for prevention and control of DENV infection are severely limited. Management of dengue-associated diseases consists of preventing the viral infection by mosquito control and relieving symptoms in the infected individuals. Development of prophylactic/therapeutic treatment against DENV infection using natural products may help address some of these current limitations. The flavone baicalein, for example, exerts potent activity against DENV adsorption to the host and post-entry viral replication. In addition, several natural products such as quercetin and narasin, as well as marine seaweed extracts have been observed to possess significant anti-DENV properties.[29,30,31] Recently, we have reported chebulagic acid and punicalagin, two hydrolysable tannins isolated from Terminalia chebula (痊d子q Hē Zǐ), as broad-spectrum antiviral agents against several viruses including DENV. Specifically, chebulagic acid and punicalagin can directly inactivate free DENV particles and interfere with the attachment and fusion events during early viral entry. Identification of these natural viral inhibitors could help the development of therapeutics against DENV infection and reduce the risks of DHF/DSS.
- ENTEROVIRUS 71 EV71 is a member of the Picornaviridae family, possessing a positive-sense ssRNA genome and is non-enveloped. EV71 is ordinarily transmitted by fecal–oral route, but transmission by respiratory droplet is also possible. It is one of the major causes of HFMD in children, is sometimes associated with severe neurological diseases, and can be fatal. The transmission rate in children under 5 years of age is typically high in endemic areas and several outbreaks have occurred over the past few decades.[33,34,35] Medication and preventive vaccines against EV71 are presently in development and palliative care is used to ameliorate the symptoms. Nevertheless, several natural products and herbal medicines have been shown to possess inhibitory activity against EV71 infection. Extracts and pure constituents of O. basilicum effectively block EV71 infection and replication. In addition, raoulic acid, which has previously been mentioned as an inhibitor to CVB, also suppresses EV71. Gallic acid from Woodfordia fruticosa flowers (碚ﾚ子q絏ﾔ Xiā Zǐ Huā) has also been observed to exert anti-EV71 activity. Finally, epigallocatechin gallate from green tea has been identified to interfere with EV71 replication via modulation of the cellular redox environment. Without efficient medical treatment for the prevention and control of infection by EV71, further studies in identifying novel antivirals against the enterovirus are encouraged.
- HEPATITIS B VIRUS HBV is the prototype virus of the Hepadnaviridae family. It is an enveloped virus possessing a relaxed circular, partially double-stranded DNA (dsDNA) genome. HBV causes hepatitis B and the infection is transmitted by exposure to blood or body fluids containing the virus. Although spontaneous recovery is common following acute hepatitis B, medication is recommended for chronic infection because of the risk of developing cirrhosis and hepatocellular carcinoma (HCC). The development of HBV vaccine and nationwide hepatitis B vaccination program in endemic countries such as Taiwan have helped control HBV infection as well as reduce the incidence of childhood HCC. Despite the existence of preventive vaccines, the present HBV-infected population, including those in areas where vaccination program is unavailable, remains at risk for end-stage liver diseases. Therapeutic treatment against HBV includes nucleotide/nucleoside analogs such as lamivudine, adefovir, tenofovir, telbivudine, and entecavir, as well as the immune modulator pegylated interferon-α (Peg-IFN-α). However, eradication of HBV from the host proves difficult once persistent infection is established, and the situation is further aggravated by risks of selecting drug-resistant viral mutants, treatment failure in non-responders, and potential future viral reactivation. Therefore, anti-HBV drug discovery is still a matter of importance for supporting current therapy and hepatitis B management program to treat some current 300-400 million carriers globally.
- INFLUENZA VIRUS The influenza A, B, and C viruses (IFA, IFB, and IFC) are enveloped, negative-sense ssRNA viruses classified in the Orthomyxoviridae family. These viruses cause respiratory infection yielding symptoms that include fever, headache, sore throat, sneezing, and muscle and joint pains, and can develop into more severe and potentially fatal conditions such as pneumonia.[107,108] IFA (most epidemic) has a wide host range including birds and humans as well as other mammals, whereas IFB seems to naturally infect humans and IFC (less frequently encountered) can be isolated from humans and swine. Influenza virus infection has produced considerable morbidity in humans. An estimated 250,000-500,000 deaths occur annually due to seasonal epidemics, and in major pandemics, this number has been observed to rise to some 20-40 million deaths, as in the case of the 1918 H1N1 Spanish Flu.[13 Despite the availability of vaccines based on predicted circulating strains, influenza viruses are known to continuously evolve their hemagglutinin (HA) and neuraminidase (NA) envelope proteins.[110,111] This variation renders any preexisting circulating antibody from earlier exposure or immunization ineffective at neutralizing the virus, hence making the host vulnerable to infection. Furthermore, potential risks of cross-species transmission and host adaptation of influenza viruses between animals and humans resulting in highly pathogenic strains have also raised concerns. Another issue is the widespread development of drug resistance, which has been observed with the first generation of anti-influenza medications, specifically the M2 ion channel blockers amantadine and rimantadine. Resistant strains against the currently approved neuraminidase inhibitors (which prevent the release of mature influenza viruses) including oseltamivir and zanamivir have also already appeared. Due to the drug resistance problems, the rapid evolution of influenza viruses, and the occurrence of several recent outbreaks (e.g., H5N1, H1N1, H7N9), more sophisticated antiviral strategies are urgently needed to prevent and control potential pandemics with emerging influenza strains. Several natural products have been examined for their effects against influenza. Standardized elderberry (接ﾚ敘木憙 Jiē Gǔ Mů; Sambucus nigra) liquid extract exerts in vitro antiviral effects against IFA, IFB, as well as respiratory bacterial pathogens. A licensed commercial extract from Pelargonium sidoides roots inhibits the entry of IFA, impairs viral hemagglutination as well as neuraminidase activity, and improves the symptoms of influenza-infected mice. The aqueous extract from dandelion (筎公恋紏p PGōng Yīng; Taraxacum officinale) impedes IFA infection and decreases its polymerase activity as well as the nucleoprotein (NP) RNA level. Spirooliganone B from the roots of Illicium oligandrum exhibits potent anti-IFA activities. A multitude of secondary plant metabolites have also been identified as potential influenza NA inhibitors, and more recent ones include chalcones from Glycyrrhiza inflata, xanthones from Polygala karensium, and homoisoflavonoids from Caesalpinia sappan (秹h木ﾘSū Mů). Further exploration of these natural anti-influenza agents for clinical application will help broaden the drug portfolio for prophylactic/therapeutic treatment of potential flu epidemics or pandemics.
- PROSPECTS AND CONCLUSION As many viruses remain without preventive vaccines and effective antiviral treatments, eradicating these viral diseases appears difficult. Nonetheless, natural products serve as an excellent source of biodiversity for discovering novel antivirals, revealing new structure–activity relationships, and developing effective protective/therapeutic strategies against viral infections. Many natural products and herbal ingredients are observed to possess robust antiviral activity and their discoveries can further help develop derivatives and therapeutic leads (e.g., glycyrrhetinic acid derivatives as novel anti-HBV agents, acetoxime derivative from the Mediterranean mollusk Hexaplex trunculus as inhibitor against HSV-1, and caffeic acid derivatives as a new type of influenza NA antagonist).[155,156,157] Our discovery of chebulagic acid and punicalagin being capable of inhibiting entry of several viruses due to their GAG-competing properties could help develop broad-spectrum antivirals for prevention and control of these viral pathogens. As many studies in this domain are only preliminary, further exploration in characterizing the bioactive ingredients, defining the underlying mechanisms, as well as assessing the efficacy and potential application in vivo is encouraged in order to help develop effective antiviral treatments. Furthermore, additional studies should also examine the possibility of combination therapies with other natural agents or with standard therapeutics, as a multi-target therapy may help reduce the risk of generating drug-resistant viruses. We believe that natural products will continue to play an important role and contribute to antiviral drug development.