Natural Compounds against RNA Viruses: Comparison
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Please note this is a comparison between Version 1 by Maria Musarra Pizzo and Version 2 by Catherine Yang.

Natural products from plants or other organisms are a rich source of structurally novel chemical compounds including antivirals. Indeed, in traditional medicine, many pathological conditions have been treated using plant-derived medicines. Thus, the identification of novel alternative antiviral agents is of critical importance. Here we summarize novel phytochemicals with antiviral activity against human viruses and their potential application in treating or preventing viral disease. 

  • viral infections
  • natural bioactive compounds
  • novel antiviral drugs

1. Human Immunodeficiency Virus (HIV)

Human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) infection leads to immunological failure and Acquired Immunodeficiency Syndrome (AIDS). HIV is a member of the lentivirus genus, which includes retroviruses that possess complex genomes. All lentiviruses are enveloped by a lipid bilayer that is derived from the membrane of the host cell. HIV-1 particles bind specifically to cells bearing the CD4 receptor, lymphocytes, and cause their destruction with a half-life of fewer than two days [1][62]. This leads to the fusion of HIV-1 to the host cell, thereby leading to the release of viral RNA into the cell. The reverse transcriptase enzyme presents in the virus (HIV-1) converts single-stranded viral RNA to double-stranded viral DNA. The formed viral DNA enters the host cell nucleus and incorporates the viral DNA within the host cell’s DNA by the viral enzyme integrase. This integrated viral DNA as provirus could reproduce few or no copies or remain inactive for many years. Since the introduction of highly active antiretroviral therapy (HAART), as well as the impact of preventive measures, the prevalence and incidence of HIV, have declined globally over the last decade except for parts of Eastern Europe and Central Asia [2][63]. However, the present therapy finds its limitations in the emergence of multidrug resistance as well as HIV persistence within latent cellular reservoirs. Compounds derived from plant, marine, and other natural products have been found to combat HIV infection and/or target HIV reservoirs, and these discoveries have substantially guided current HIV therapy-based studies. Accordingly, finding new drugs and novel targets is needed to treat infected people and to eliminate HIV reservoirs in order to ultimately block HIV infection. Recently, several anti-HIV compounds obtained from natural products have been extensively reported [3][64]. However, a limited number of those are in the advanced development stage associated with well-known mechanisms of action [4][65] (Table 15).
Table 15. Natural compounds and their antiviral targets against Immunodeficiency virus.
Natural Source Compound Immunodeficiency Virus Target CC50 EC50-IC50 SI Reference
Griffithsia sp. Griffithsin HIV Entry inhibitors   0.043–0.63 nM   [5][66]
Nostoc ellipsosporum Ascyanovirin-N HIV       [6][67]
Siliquariaspongia mirabilis

Stelletta clavosa Mirabamide-A HIV   40–140 nM   [7]
CC50: Half maximal cytotoxic concentration; EC50-IC50: Half maximal inhibitory concentration; SI: Selectivity index = CC50/IC50.

2. Influenza Viruses

Influenza viruses are negative-stranded, segmented RNA viruses, and are members of the Orthomyxoviridae family. Influenza viruses comprise three types (A, B, and C), while type A is divided into different subtypes which are distinguishable by antigenicity of their surface glycoproteins, haemagglutinin (HA), and neuraminidase (NA) [16][79]. Influenza viruses, based on their genetic mutations can be categorized into two different entities: seasonal or pandemic representing a major public health problem, with high rates of morbidity and mortality [17][80]. Airway epithelial cells lining the respiratory mucosa are the primary target of influenza infection. The recognition of influenza virus antigens through antigen-presenting cells and pattern recognition receptors (PRRs) can consequently upregulate several correspondent downstream molecules including interleukin-6 (IL-6), IL-1β, and tumour necrosis factor α (TNF-α) which causes influenza mediated signs and symptoms [18][81]. To date, anti-influenza drugs include M2 ion channel inhibitors and neuraminidase inhibitors [19][82]. M2 ion channel inhibitors, such as amantadine and rimantadine, act as inhibitors of the uncoating process, which is essential for the release of the virus into the cytoplasm. Neuraminidase inhibitors, including oseltamivir and zanamivir, are directed against the enzymatic activity of neuraminidase, which assures the release of progeny viruses from infected cells. It has been suggested that herbal medicines might be beneficial in the prevention or management of seasonal or pandemic influenza (Table 26). An in vitro study showed that oligonol extracted from lychee fruit (Litchi chinensis) inhibits proliferation of influenza virus H3N2 by blocking reactive oxygen species (ROS)-dependent ERK (extracellular-signal-regulated kinases) phosphorylation [20][83]. Another in vitro investigation showed that green tea catechins possess higher inhibitory effects on the endonuclease activity of influenza A virus RNA polymerase [21][84]. Slaine and collaborators showed that the macrolide pateamine A (from Mycale hentscheli) and the rocagalte silvestrol (from Aglaia), two inhibitors of the eukaryotic initiation factor-4A (eIF4A), caused the block of influenza A viral protein synthesis as well as the failure of the viral genome replication [22][85]. The inhibitory effect of silvestrol was fully reversible while the pateamine A irreversibly binds to eIF4A and caused the inhibition of genetically divergent influenza A strains replication [22][85].
Table 26.
Natural products against Influenza viruses.
Natural Source Compound Influenza

Viruses		 Target CC50 EC50-IC50 SI Reference
Litchi chinensis Oligonol H3N2 Blocking (ROS)-dependent ERK

phosphorylation		       [20][83]
Green tea Catechins H1N1 Inhibiting RNA

polymerase		       [21][84]
Aglaia Silvestrol H1N1 Inhibitors of the

cellular factor eEIF4A		  [68]

50.

Natural Products as Hemagglutinin Inhibitors

Given the rapid emergence of drug-resistant influenza virus strains, hemagglutinin (HA) is a promising target for developing anti-influenza drugs. HA is an envelope protein that plays a critical role in viral binding, fusion and entry processes. Curcumin showed anti-influenza activity against influenza viruses PR8, H1N1, and H6N1. The results showed more than a 90% reduction in virus yield in cell culture using 30 μM of curcumin. The plaque reduction test elicited the approximate EC50 of 0.47 μM for curcumin against influenza viruses [23][86]. In H1N1 and also H6N1 subtypes, the inhibition of HA interaction reflected the direct effect of curcumin on infectivity of viral particles and this has proved by the time of the drug addiction experiment [23][86]. An in vitro investigation indicated that Cistus incanus, a member of the Cistaceae family, has anti-influenza virus activity in A549 (human lung epithelial cell) or MadinDarby canine kidney (MDCK) cell cultures infected with prototype avian and human influenza strains of different subtypes by the reduction of progeny virus titers of up to two logs without any toxicity [24][87]. Furthermore, the binding of the polyphenol components of the extract to the virus surface showed protective effects through inhibition of HA binding to cellular receptors [24][87]. In another study, Cistus incanus exhibited antiviral activity against a highly pathogenic avian influenza A virus (H7N7) in both cell cultures and a mouse infection model [27][88]. Haidari and colleagues indicated that punicalagin from Punica granatum polyphenol-rich extract had anti-influenza properties in MDCK and chicken red blood cells (cRBC) infected by human influenza A (H3N2) through inhibiting the virus replication as well as inhibiting virus-induced agglutination of cRBCs [25][89]. Furthermore, an investigation showed that epigallocatechin gallate (EGCG) and theaflavin digallate (TF3) from green tea and black tea respectively, inhibit the infectivity of both influenza A and B viruses in MDCK cells through binding to virus HA and prevention of virus adsorption to MDCK cells [26][90].

3. Hepatitis C Virus

Hepatitis C virus (HCV) is an enveloped, positive-sense single-stranded RNA virus belonging to the Flaviviridae family. The HCV genomic RNA encodes a polyprotein that is then cleaved by both the host and virus proteases into mature proteins. The nonstructural proteins; NS2, NS3, NS4A, NS4B, NS5A, and NS5B, core proteins, glycoproteins E1, and E2; the ion channel p7 (Banerjee et al. 2010). The (NS5B), an RNA-dependent RNA polymerase (RdRp) is responsible for replicating the viral RNA genome [28][91]. Infected individuals have treated with standard treatment, consisting of PEGylated (PEG)-interferon (IFN)-α in combination with ribavirin (RBV) for over a decade. Recently, several protease inhibitors such as boceprevir and telaprevir have been approved as treatments for hepatitis C. However, these new inhibitors are associated with drug toxicity and the development of resistant mutants [29][92]. Based on this, many phytochemical constituents have been identified that display considerable inhibition of the HCV life cycle at different steps (Table 37).
Table 37.
Natural products against the Hepatitis C virus.
Natural Source Compound HCV Target CC50

(µg/mL)		 EC50-IC50 (µg/mL) SI or TI Reference
Reference
Trichilia dregeana
Lagerstroemia

speciosaRoot extract L.HCV Inhibition of viral entry Orobol 7-O-d-glucoside (O7G) Human rhinovirus A

Human rhinovirus B		 Broad

spectrum

antiviral

  activity16.6 37 100[30] 0.58-8.80[94]
12 [42][ Detarium

microcarpum Stem bark extract   1.42 211
109]
Ocimum basilicum Crude aqueous extracts Coxsackievirus B1

Enterovirus 71		 1469.3 105.7 ± 2.6

200.2 ± 3.2		 13.9

7.3		 [43][61]     Phragmanthera

capitata Leave extract   13.17  [
Ocimum basilicum Ethanolic extracts Coxsackievirus B1

Enterovirus 71		22][85] 684.8 146.3 ± 2.9

198.9 ± 1.8		 4.7

3.4		 Syzygium claviflorum Betulinic acid Dihydro betulinic Bupleurum kaoi Saikosaponin B2HIV Maturation inhibitors   740.4 ± 28.35 µM 16.13 ± 2.41 µM1.4 µM

0.9 µM		 9.3

14		 [8]
Woodfordia fruticosa Gallic acid Enterovirus 7145.9[69]
Mycale hentscheli Pateamine A H1N1

H3N2		       [31][95]
100 0.76 132 [44][110] Synthetic derivative of betulinic acid Bevirimat HIV 25 μM 7.8 nM >2500 [ Bupleurum kaoi9][70]
Curcuma longa L. Curcumin H1N1
Raoulia australisMethanolic extractH6N1 16.82 ± 1.89 Raoulic acid Human rhinovirus 2

Human rhinovirus 3215.4 ± 10.7

Coxsackievirus B3

Coxsackievirus B4

Enterovirus 71		Haemagglutinin

inhibitors		 43 µM 0.47 µM 92.5 [23] 201.7812.8


65.86[ 0.1

0.19

0.33

0.40

0.1		   [45][46][111,86] 112] Rheum palmatum Sennoside A HIV
Cistus incanus Polyphenol rich extractReverse transcriptase and Integrase inhibitors   A549   50 μg/mL      Anthocyanidin Delphinidin
Ocimum basilicum Ursolic acid  3.7 ± 0.8 μM Targets viral structures and inhibits viral infection and

  Coxsackievirus B1

Enterovirus 71		replication

process		[32][96][24][87[10][71]
] Morus nigra Kuwanon-L
Punica granatum        Punicalagin
[11][72]
H3N2     Alloeocomatella polycladia Ethyl acetate-

soluble fraction		  Suppression of the

helicase activity of

HCV NS3		  [25 11.7 ± 0.7][89]   [33][ Justica gendarussa Patentiflorin A HIV  
Green tea Epigallocatechin gallate H1N124−37 nM        [12][73]
97] [
Fusarium equiseti Crude extracts Inhibition of HCV NS3/4A protease26   19–77 µM]  [90] [34][98] Calophyllum lanigerum Calanolides HIV   0.1–0.4 µM   [13][74]
Eclipta alba Aqueous extract Inhibition of HCV

NS5B replicase activity		   11   [35][99] Euphorbia kansui Ingenol

Bryostatin

Prostratin		 HIV Latency-reversing agents (LRAs)       [14][77]
Taraxacum officinale Flavonoids   [36][100] Theobroma cacao Procyanidin C1-flavonoids HIV       [15][78]

CC50: Half maximal cytotoxic concentration; EC50-IC50: Half maximal inhibitory concentration; SI: Selectivity index = CC50/IC

Panax ginseng
Ginsenosides
Hepatitis virus A
 
 
 
[
61
]
[
133
]

CC50: Half maximal cytotoxic concentration; EC50-IC50: Half maximal inhibitory concentration; SI: Selectivity index = CC50/IC50.

5. Norovirus

Human noroviruses (HuNoVs) are the leading cause of gastroenteritis and severe childhood diarrhea worldwide [62][135]. Noroviruses belong to the family Caliciviridae, members of which have a small, single-stranded positive-sense RNA genome. Norovirus utilizes cell surface molecules as mediators for binding and cellular entry. Murine norovirus (MNV-1) and feline calicivirus (FCV) were successfully grown and served as a surrogate model system for HuNoV [63][136]. Several medicinal plants and herb extracts were screened for antiviral activity against MVN-1 and FCV as a surrogate of norovirus (Table 59). The work of Lee and colleagues showed that the components of Morus alba L. possess antiviral effects against foodborne enteric virus surrogates. It was found that Morus alba juice and its fractions inhibit the internalization and replication of MNV-1 as well as the internalization of FCV-F9 virions [64][137]. Black raspberry juice (Rubus coreanus) was found to decrease MNV-1 plaque formation by blocking viral entry into the cell and inhibiting its internalization or through direct effects on viral particles or host cell receptors [65][138]. Green tea polyphenolic chatechins from Camellia sinensis exhibited anti-FCV-F9 antiviral activity with epigallocatechin gallate showing the best combination of antiviral activity and low cytotoxicity [66][139]. The essential oil from oregano (Origanum vulgare) decreased FCV-F9 and MNV-1 replication in a dose-dependent manner. Besides, it has been shown that oregano essential oil and its primary component carvacrol caused the loss of viral capsid integrity of MNV-1 virions as determined by transmission electron microscopy experiments [67][140]. Persimmon (Diospyros kaki) extracts containing persimmon tannin was found to reduce noroviral genome replication with no cytotoxicity effect [68][141].
Table 59.
Natural products against Noroviruses.
Natural Source Compound Noroviruses Target CC50 EC50-IC50 SI Reference
Morus alba L Juice MNV-1

FCV-F9		 Inhibiting

internalization and replication		 >0.1%

>2.5%		 0.005%

0.25%		 20

10		 [64][137]
Camellia sinensis Epigallocatechin gallate FCV-F9   12 mg/mL   [66][139]
Rubus coreanus Juice MNV-1       [65][138]
Origanum vulgare Carvacrol MNV-1       [67][140]
Diospyros kaki Persimmon tannin HuNoV Reduce genome

replication		       [68][141]
100.5 0.4 ± 0.1

0.5 ± 0.2 251

201 [43][61]
Silybum marianum Silymarin Enterovirus 71 160.20 ± 1.56 7.99 ± 3.0 20.05 [47][113]
Macaranga barteri DCM fraction Echoviruses E7

Echoviruses E19		 0.18 7.54 × 10−6

1.75 × 10		−6 19.9

8581.24		 [48][114]
Syzygium

brazzavillense Aqueous extract Coxsackievirus B4 2800 0.8   [49][116]
Rheum palmatum Ethanol extract Coxsackievirus B3   4 10 [50][117]
Swietenia macrophylla 3-hydroxy caruilignan C Reduction of HCV

protein and HCV- RNA levels
Lagerstroemia  10.5 ± 1.2μM  

speciosa L.[37][101 Quercetin-7-glucoside (Q7G) Human rhinovirus 2 >100 4.85–0.59 >20.62]
[51][118] Entada africana Methylene

chloride-methanol (MCM) stem

bark crude extract		 Broad antiviral activity
Salvia miltiorrhiza Rosmarinic acid Enterovirus A71  453 ± 0.00117   [38][102]
327.68 ± 14.43 31.57–114 2.87–10.36 [52][119] Grapeseed Phenolic

compounds		 Suppression of HCV-

induced Cox-2
Green tea Epigallocatechin-3-gallate (EGCG)  7.5 ± 0.3   [39][104]
Hepatitis virus A       [53][130] Flavanone Naringenin Release/Assembly  
Vitis vinifera Grapeseed

109 μM   [40][107]
CC50: Half maximal cytotoxic concentration; EC50-IC50: Half maximal inhibitory concentration; SI: Selectivity index = CC50/IC50.

4. Picornaviruses

The family Picornaviridae currently contains 147 species grouped into 63 genera. Viruses in the family Picornaviridae have non-enveloped particles with a single-stranded RNA (ssRNA) genome and include numerous human pathogens such as poliovirus, enterovirus 71, foot and mouth disease virus (FMDV), hepatitis A virus and rhinovirus. The broadly studied and most well-characterized group is represented by an enterovirus, including enterovirus A71 (EV71), coxsackievirus, poliovirus, and rhinovirus. The viral infection initiates by attaching to a receptor on the host cell plasma membrane and viruses belonging to different genera use different receptors to bind to and infect cells, thus exhibiting a different tissue tropism [41][108]. The antiviral drugs used in the picornaviruses treatment target virus entry (pleconaril, WIN54954 and CAR-Fc), the viral translation and/or transcription (antisense oligodeoxynucleotide and short interfering RNA) or intracellular signalling pathway (immune response activators) but do not completely eradicate the infection. To date, the antiviral activity of several natural products and herbal medicines have been tested against various picornavirus (Table 48).
Table 48.
Natural compounds and their antiviral targets against Picornaviruses.
Natural Source Compound Picornaviruses Target CC50

(µg/mL)		 EC50-IC50

(µg/mL)		 SI
extract (GSE)
Hepatitis virus A
 
 
 
[
54
]
[55][131,132]
Lagerstroemia

speciosa L. Tannin ellagic acid Human rhinovirus 2

Human rhinovirus 3

Human rhinovirus 4		 Targets host cellular factors >100 38 ± 3.2

31 ± 5.2

29 ± 2.5		 >2.6

>3.2

>3.4		 [56][120]
Bupleurum kaoi Roots extract Coxsackievirus B1 883.56 50.93   [57][121]
Mix of seven

medicinal herbs		 Xiao chai hu tang Coxsackievirus B1 945.75 50.93 18.92 [58][122]
Ornithogalum

saundersiae Orsaponin (OSW-1) Enterovirus 71, Coxsackievirus A21 Human rhinovirus 2 >100 nM 2.4–9.4 nM   [59][60][123,124]

CC50: Half maximal cytotoxic concentration; EC50-IC50: Half maximal inhibitory concentration; SI: Selectivity index = CC50/IC50.

 
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