Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development
Abstract
:1. Introduction
2. Epidemiology and Pathogenesis of HSV Infection
3. Natural Products-Derived Molecules with Anti-HSV-1 and Anti-HSV-2 Properties
4. Natural Products Targeting Enzymes Implicated in HSV Replication
5. General Discussion
6. Take-Home Messages
7. Concluding Remarks and Future Insights
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source | |
---|---|---|---|---|---|
Flavonoids | Epicatechin (1) | MTT cell viability ACV SI = 4.5 | HSV-1, SI = 6.0 (29-R) | Dietary phenolics | [26] |
Epigallocatechin (2) | HSV-1, SI = 5.2 (KOS), 12.8 (29-R) | ||||
Robinetinidol(4α-6)gallocatechin (3) | HSV-1 SI = 5.2 (KOS), 5.0 (29-R) | ||||
Apigenin (4) | CPE, PRA, YRA ACV for HSV-1 EC50 = 50 μM, SI = 10; HSV-2, EC50 = 50 μM, SI = 10 | HSV-1, EC50 = 5 μM, SI = 50; HSV-2, EC50 N/A, SI N/A | Dietary phenolics, green tea, propolis, some flavonoid rich medicinal plants. Flavanols and flavonols appear to be more active than flavones. Furthermore, treatment of Vero cells with ECG (8) and galangin (11) before virus adsorption led to a slight enhancement of inhibition, indicating that an intracellular effect may be involved. | [27] | |
Baicalin (5) | HSV-1 EC50 = 5 μM, SI= 200; HSV-2 EC50 N/A, SI N/A | ||||
Catechin hydrate (6) | HSV-1, EC50 = 4 μM, SI = 250; HSV-2, EC50 N/A, SI N/A | ||||
Chrysin (7) | HSV-1 EC50 = 2.5 μM, SI= 4; HSV-2 EC50 N/A, SI N/A | ||||
Epicatechin (1) | HSV-1, EC50 = 2.5 μM, SI = 40; HSV-2, EC50 = 35 μM, SI = 2.9 | ||||
Epicatechin gallate (8) | HSV-1, EC50 = 4 μM, SI = 125; HSV-2, EC50 = 63 μM, SI = 7.9 | ||||
Epigallocatechin (2) | HSV-1, EC50 = 2.5 μM, SI = 100; HSV-2, EC50 N/A, SI N/A | ||||
Epigallocatechin gallate (9) | HSV-1, EC50 = 2.5 μM, SI = 40; HSV-2, EC50 N/A, SI N/A | ||||
Fisetin (10) | HSV-1 EC50 2.5 μM, SI = 40; HSV-2 EC50 N/A, SI N/A | ||||
Galangin (11) | HSV-1 EC50 2.5 μM, SI = 400; HSV-2 EC50 N/A, SI N/A | ||||
Genistein (12) | HSV-1 EC50 5 μM, SI = 50; HSV-2 EC50 50 μM, SI = 5 | ||||
Kaempferol (13) | HSV-1 EC50 15 μM, SI = 3.3; HSV-2 EC50 N/A, SI N/A | ||||
Luteolin (14) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 N/A, SI N/A | ||||
Myricetin (15) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 N/A, SI N/A | ||||
Naringenin (16) | HSV-1 EC50 4 μM, SI = 187.5; HSV-2 EC50 22.5 μM, SI 33.3 | ||||
Naringin (17) | HSV-1 EC50 2.5 μM, SI = 400; HSV-2 EC50 N/A, SI N/A | ||||
Rutin (18) | HSV-1 EC50 5 μM, SI = 2000; HSV-2 EC50 N/A, SI N/A | ||||
Quercetin (19) | HSV-1 EC50 5 μM, SI = 20; HSV-2 EC50 35 μM, SI = 2.9 | ||||
Quercetin (19) | Raw 264.7 and Vero cells, HSV-1 PRA, Western blot analysis, quantitative RT-PCR | Reduction in plaque formation of 90% at 30 µg/mL | Inhibition of the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52). Specific suppression of the expression of TLR-3, inhibition of transcriptional factors NF-κB and IRF3. | [28] | |
Epigallocatechin gallate (9) | IP (%) | IP: 100% | Dietary phenolic, green tea component | [29] | |
% PFU | At 1 μM cca 40%, at 5 µM cca 5% | [30] | |||
Houttuynoid M (20) | PFA ACV IC50 0.15 μM; SI>1333 | IC50 17.72 μM; SI> 11.29 IC50 12.42 μM; SI> 16.10 | Houttuynia cordata | [31] | |
Houttuynoid A (21) | |||||
1. β-galactosidase assay - the activity of enzyme measured in cell lysates 2. PRA 3. Progeny HSV-1 yield assay - effect on HSV-1 multiplication | 1. HSV-1 (F) IC50 23.50 ± 1.82 μM, CC50 166.36 ± 9.27 μM 2. HSV-1 (F) IC50 of 21.08 μM 3. HSV-1 (F) multiplication reduced by 100% at 75 μM | Possible mechanism—blocking viral membrane fusion | [32] | ||
Genistein (12) | Vero cells, HSV-1 (KOS), HSV-1 (29 R), HSV-2 (333) PRA ACV: IC50 2.44 μM, SI >1818 (KOS), NA (29 R), IC50 3.30 μM, SI >303 (333) | IC50 (μM); SI: HSV-1 (KOS)/HSV-1 (29 R)/HSV-2 (333) 14.02, 3.88/7.76, 7.01/14.12, 6.95 | Isoflavonoid, soya beans, alfalfa | [33] | |
Kuwanon C (22) | Vero cells, HSV-1 PRA ACV IC50 1.45 μg/mL; SI 144.8 | HSV-1 IC50 0.91 ± 0.43 μg/mL; SI 230.8 | In silico analysis along with antibacterial and anti-inflammatory effects | [34] | |
Kuwanon T (23) | HSV-1 IC50 0.64 ± 0.52 μg/mL; SI 328.1 | ||||
Kuwanon U (24) | HSV-1 IC50 1.93 ± 1.13 μg/mL; SI 108.8 | ||||
Kuwanon E (25) | Vero cells, HSV-2 TRA ACV IC50 1.65 μg/mL; SI 127.3 | HSV-2 IC50 1.61 ± 0.31 μg/mL; SI 130.4 | |||
Luteoforol (26) | Vero cells, HSV-1 (KOS, VR733) CPE as 50% tissue culture infective dose (TCID50/50 μL) ACV reduced the titer by 3.16 log10 against strain KOS and by 3 log10 against strain VR733 | Reduced the titer by 2.9 log10 against strain KOS and by 3.18 log10 against strain VR733 | Hypericum connatum | [35] | |
Luteolin (14) | Vero cells, HSV-2 PRA ACV EC50 2.6 μg/mL, SI= 42.53 | HSV-2 EC50 22.4 μg/mL, SI = 12.43 | Dietary flavonoid | [36] | |
Theaflavin-3,3′-digallate (27) | Vero cells, HSV-1 PRA Flow cytometry antiviral assay Fluorescence confocal microscopy | EC50 20 μM; SI = 5.625 | Green tea | [37] | |
Cycloartocarpin (28) | Vero cells, HSV-1 (KOS), HSV-2 (186) PRA ACV HSV-1 IC50 1.5 μM; HSV-2 IC50 2.9 μM | HSV-1 IC50 28.2 μM; HSV-2 IC50 23.5 μM | Prenylated phenolics Morus spp., Artocarpus spp. | [38] | |
Isocyclomorusin (29) | HSV-1 IC50 30.4 μM; HSV-2 IC50 27.2 μM | ||||
Norartocarpetin (30) | HSV-1 IC50 63 μM; HSV-2 IC50 52.2 μM | ||||
Catechin-7-gallate (31) | Vero cells, HSV-1 CPE ACV CC50 >200 ± 0.4 μg/mL | CC50 43.2 ± 2.3 μg/mL | Dietary phenols Low activity, questionable results. | [39] | |
Kaempferol-3-O-6′´-O-galloyl-β-D-glucopyranoside (32) | CC50 124.1 ± 1.2 μg/mL | ||||
Kaempferol (13) | CC50 76.1 ± 0.2 μg/mL | ||||
Quercetin-3-O-6´´-O-galloyl-β-D-glucopyranoside (33) | CC50 175.6 ± 0.9 μg/mL | ||||
Quercetin (19) | CC50 78.1 ± 0.8 μg/mL | ||||
7-O-galloyltricetiflavan (34) | Vero cells, HSV-1 CPE ACV IC50 0.25 μg/mL | IC50 30 μg/mL | Pithecellobium clypearia Other viruses tested | [40] | |
7,4′-di-O-galloyltricetiflavan (35) | IC50 20 μg/mL | ||||
Strychnobiflavone (36) | Vero cells, HSV-1 (KOS), HSV-2 (333) PRA Post infection treatment ACV HSV-1 IC50 1.38 μg/mL, SI > 1.449; HSV-2 IC50 3.23 μg/mL, SI > 619 | HSV-1 (KOS) IC50 11.82 μg/mL, SI = 22.61; HSV-2 (strain 333) IC50 6.31 μg/mL, SI = 42.33 | Strychnos pseudoquina | [41] | |
Derivatives of phenolic acids | Ethyl 2,4-dihydroxybenzoate (37) | Vero cells, HSV-1 PRA ACV IC50 1.45 μg/mL; SI 144.8 | HSV-1 IC50 1.32 ± 0.44 μg/mL; SI 159.1 | In silico analysis; antibacterial and anti-inflammatory effects | [34] |
Gallic acid (38) | Vero cells, HSV-1 CPE ACV CC50 > 200 ± 0.4 μg/mL | CC50 49.8 ± 0.4 μg/mL | Dietary phenols Low activity, questionable results. | [39] | |
IP (%) | IP: 100 % | Dietary phenolics | [29] | ||
Alkyl derivatives of gallic acid Octyl gallate (39) | HEp-2 and Vero cells, HSV-1 CPE | Octyl gallate directly inactivates HSV-1 (virucidal activity). 39 suppresses both the intracellular multiplication and the release of the virus. 39 selectively accelerates the death of the virus-infected cells. The addition of the compound (39), even at 6 h post-infection, completely abolished the formation of progeny virus in the infected cells. | Other viruses tested including HSV-1: Inhibition was enhanced by the compounds with a higher number of carbons in the alkyl moieties, maximum at 12 (lauryl gallate), however, cytotoxicity was increased. | [42] | |
Chebulagic acid (40) | IPF ACV IC50 29.04 ± 1.04 μg/mL | HSV-2 IC50 1.41 ± 0.51 μg/mL | Dose-dependently potent in vitro direct anti-viral activity. Effective prevention of the attachment as well as penetration of the HSV-2 to Vero cells. | [43] | |
Chebulinic acid (41) | HSV-2 IC50 0.06 ± 0.002 μg/mL | ||||
Tellimagrandin I (42) | IPF At 0.75 μg/mL ACV completely protected Vero cells against infection | EC50 of 2.6 μM for the direct mode, 5.0 μM for the absorption mode. | Ellagitannin—Cornus spp., Eucalyptus spp., Melaleuca styphelioides | [44] | |
N-trans-ferulolyl tyramine (43) | IP (%) | IP: 100% | Dietary phenolics | [29] | |
Protocatechuic acid (44) | Vero cells, HSV-2 ACV EC50 1.43 μg/mL, SI= 140 | EC50 0.92 µg/mL, SI = 217 | Dietary phenolic, metabolite of gut degradation of phenolics | [45] | |
Psoromic acid (45) | Vero cells, HSV-1, HSV-2 ACV for HSV-1 IC50 2.6 μM; SI 119.2; for HSV-2 EC50 2.8 μM; SI 110.7 | HSV-1 IC50 1.9 μM; SI 163.2 HSV-2 EC50 2.7 μM; SI 114.8 | Study of synergy with ACV and inhibition of HSV-1 DNA polymerase (in vitro and in silico assays). | [46] | |
Rhinacanthinic acid C (46) | Vero cells, HSV-2 PRA ACV ED50 14.67 μg/mL | ED50 58.98 μg/mL | Rhinacanthus nasutus | [47] | |
Anthrones | Antrodin A (47) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 IC50 2.1 μg/mL, SI = 61.9, HSV-2 IC50 2.9 μg/mL, SI = 44.8 | HSV-1 IC50 5.8 μg/mL, SI= 18.97, HSV-2 IC50 5.5 μg/mL, SI= 20.0 | Antrodia camphorate Additive effect of 47 with ACV | [48] |
Aspergilol H (48) | HSV-1 PRA ACV EC50 3.0 μM | HSV-1 EC50 4.68 μM | Deep-sea fungus Aspergillus versicolor | [49] | |
Aspergilol I (49) | HSV-1 EC50 6.25 μM | ||||
Coccoquinone A (50) | HSV-1 EC50 3.12 μM | ||||
Stilbenoids and 2-arylbenzofurans | Kuwanon X (51) | Vero cells, HSV-1 (15577 and clinical strains), HSV-2 (333) PRA ACV IC50 0.1 µg/mL for all strains | HSV-1 IC50 2.2 and 1.5 μg/mL; HSV-2 IC50 2.5 µg/mL | Prenylated phenol, Morus spp. 51 did not inactivate cell-free HSV-1 particles but inhibited cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, 51 reduced the expression of HSV-1 IE and L genes and decreased the synthesis of HSV-1 DNA. Furthermore, 51 inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. | [50] |
Mulberrofuran B (52) | Vero cells, HSV-2 TRA ACV IC50 1.65 μg/mL; SI 127.3 | HSV-2 IC50 0.93 ± 0.23 μg/mL; SI 225.8 | In silico analysis; antibacterial and anti-inflammatory effects | [34] | |
Oxyresveratrol (53) | Vero cells, HSV-1 (KOS), HSV-2 (186) PRA ACV HSV-1 IC50 1.5 μM; HSV-2 IC50 2.9 μM | HSV-1 IC50 42.8 μM; HSV-2 IC50 42.5 μM | Stilbenoid Morus spp., Artocarpus spp. | [38] | |
Other phenolics | Coniferyl aldehyde (54) | Vero cells, HSV-1, HSV-2 ACV HSV-1 EC50 0.8 μg/mL | HSV-1 EC50 6.39 μg/mL, SI = 78.3 HSV-2 EC50 41.2 μg/mL, SI = 12.1 | Phenolic, Quercus suber, Simira glaziovii, S. eleiezeriana | [51] |
Coumestrol (55) | Vero cells, HSV-1 (KOS), HSV-1 (29 R), HSV-2 (333) PRA ACV: IC50 2.44 μM, SI >1818 (KOS), NA (29 R), IC50 3.30 μM, SI >303 (333) | IC50 (μM), SI: HSV-1 (KOS)/HSV-1 (29 R)/HSV-2(333) 11.62, 9.6/3.34, 31.52/35.53, 28.14 | Coumestan, soya beans, alfalfa | [33] | |
Curcumin (56) | CPA, PRA, viral adsorption assay, viral penetration assay | At 30 µM, 85% inhibition of HSV-1 and 68% of HSV-2 CPE, PRA 92% for HSV-1 and 88% for HSV-2 | Curcuma longa Inhibits HSV adsorption and replication | [52] | |
Vero cells, HSV-1 CPE ACV CC50 > 200 ± 0.4 μg/mL | CC50 49.8 ± 0.4 μg/mL | Dietary phenols Low activity, questionable results | [39] | ||
Imperatorin (57) | Vero cells, HSV-1 CPE ACV – full inhibition of replication of HSV-1 at 250 μg/mL | 57 decreases titer of HSV-1 by 55.6% at 31.25 μg/mL | Furanocoumarin of Apiaceae family | [53] | |
Pinoresinol (58) | IP (%) | IP: 26% | Dietary phenolics | [29] |
Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source |
---|---|---|---|---|
Harmine (59) | Vero cells, HSV-2 PRA ACV CC50 and IC50 > 3.000 mg/mL and 0.1 μg/mL, respectively, SI > 30.000 | CC50 and IC50 12.5 μg/mL and 0.3 μg/mL, respectively, SI = 41.6 | Peganum harmala, Banisteriopsis caapi, Passiflora incarnata | [54] |
Human foreskin fibroblasts (HFF), HSV-1 (166vVP22-GFP) GFP-based reporter assay Cidofovir at 3 μM reduced to 20% | At 3.3 μM, 59 reduced HSV-1 replication to approx. 50%, at 10 μM to approx. 5% | 59 inhibited viral protein expressed as a dual-specificity tyrosine phosphorylation-regulated kinase inhibitor. | [55] | |
Harmane (60) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 EC50 0.8 μg/mL | HSV-1 EC50 4.9 μg/mL, SI = 11.8 HSV-2 EC50 71.8 μg/mL, SI = 24.7 | P. harmala, B. caapi, P. incarnata | [51] |
Aaptamine (61) (8,9-dimethoxy-1H-benzo[d,e][1,6]-naphthyridin) | Vero cells, HSV-1 CPE | EC50 7.0 µg/mL | Marine sponge Aaptos spp. | [56] |
Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source | |
---|---|---|---|---|---|
Monoterpenes | Geraniol (62) | Vero cells, HSV-2 ACV (EC50 1.94 µg/mL; SI = 108.25 | HSV-2 EC50 1.92 µg/mL SI = 109.38 | Thymus bovei Benth. essential oil, typical monoterpene of Lamiaceae | [57] |
Cypellocarpin C (63) | Vero cells, HSV-1 (KOS), HSV-2 (clinical isolates) PRA, TRI ACV HSV-1 IC50 1.92 ± 0.23 μg/mL, SI >109.4, HSV-2 IC50 1.75 ± 0.33, SI > 120.0 | HSV-1 IC50 0.96 ± 0.12, SI > 218.8 | 63 is a cross-metabolite of monoterpenic glycoside and a methylchromone), Eucalyptus globulus | [58] | |
(+)-rhodonoid C (64) | Vero cells, HSV-1 CPE ACV IC50 4.2 μM, SI > 100 | IC50 80.6 ± 4.7 μM, SI = 2.7 | 64 is a cross-metabolite of monoterpene and polyketide Rhododendron spp. | [59] | |
Sesquiterpenes | β-caryophyllene (65) | Vero cells, HSV-1, HSV-2 (clinical isolates), (HSV-2 ACV-resistant) PRA Time-of-addition assay Virus inactivation assay ACV HS2-2 0.14 μg/mL; SI = 1178; HSV-2 (acyclovir-resistant) EC50 71.84 μg/mL, SI = 2.29 | HSV-2 EC50 5.38 μg/mL, SI = 9.10 HSV-2 (acyclovir resistant) EC50 5.02 μg/mL, SI = 9.76 | Bicyclic sesquiterpene, common occurrence, for example, cloves | [60] |
Kellerin (66) | Vero cells, HSV-1 (KOS) PRA ACV at 2.5 µg/mL, 82% of plaque reduction | 66 at 2.5 µg/mL, 65% | 66 is a cross-metabolite of sesquiterpene and coumarin Gum resin of Ferula assa foetida No cytotoxic effect up to 10 µg/mL | [61] | |
Lactarorufin A 8-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (67) | Vero cells, HSV-1 (MacIntyre strain) CPE ACV IC50 1 µg/mL, SI ˃ 250 | HSV-1 IC50 17.3 µg/mL, SI = 16 | Taxol-N-benzoylphenyl-isoserinates of sesquiterpenoid alcohols and sesquiterpenoids Lactarius mushroom | [62] | |
Isolactarorufin 8-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (68) | HSV-1 IC50 21.9 µg/mL, SI = 17.4 | ||||
Furandiol 8-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (69) | HSV-1 IC50 15 µg/mL, SI = 19.3 | ||||
Isovellerol 13-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (70) | HSV-1 IC50 7.8 µg/mL, SI = 13.9 | ||||
5-deoxylactarolid B 8-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (71) | HSV-1 IC50 3.4 µg/mL, SI = 31.7 | ||||
Isolactarorufin 8-epi-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (72) | HSV-1 IC50 4.2 µg/mL, SI = 18.4 | ||||
Alantolactone (73) | Vero cells, HSV-1 CPE Ribavirin as a positive control | At 10-6–10-8 g/mL showed an antiviral effect | Sesquiterpene Inula helenium | [63] | |
(-)-15-methoxy-3,6-peroxocupar-1-ene (74) | Vero cells, HSV-1 (KOS strain, VR-1493) PRA ACV at 2.5 μM 96.96% | Anti HSV-1at 10 μg/mL 43.93 % | Sesquiterpene Schisandra sphenanthera | [64] | |
(R)-6,9-dihydroxy-1-oxo-14-noreudesm-5,7,9-triene (75) | Vero cells, HSV-2 CPE inhibition method Quantitative PCR | 2 log10 reduction in HSV-2 yield at conc. 12.5 µM, IC50 6.25 μM | 14-Noreudesmane sesquiterpene Elaeagnus rhamnoides | [65] | |
Diterpenes | Simirane A (76) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 EC50 0.8 μg/mL | HSV-1 EC50 4.61 μg/mL, SI = 7.01 HSV-2 EC50 3.73 μg/mL, SI = 8.7 | Erythroxylane diterpene, Simira eliezeriana | [51] |
Dodovisnoid D (77) | Vero cells, HSV-1 CPE ACV IC50 4.2 μM, SI > 100 | IC50 5.5 μM, SI = 2.8 | Clerodane diterpenes Dodonaea viscosa | [66] | |
Dodovisnoid F (78) | IC50 23.0 μM, SI = 4.7 | ||||
Atomaric acid (79) | Vero cells, HSV-1 (ACR-29) CPE ACV EC50 1.2 μM, SI > 716.6 | EC50 1.28 µM, SI > 353.1 | Meroditerpenes from Brazilian seaweed Stypopodium zonale (Dictyotales) Atomaric acid (79) and epitanodiol (80) may be selectively targeted to HSV-1 replication Low effect on HIV-1 reverse transcriptase | [67] | |
Epitaondiol (80) | EC50 1.34 µM, SI > 361.9 | ||||
10-deacetyl-baccatin III (81) | Vero cells, HSV-1 (MacIntyre strain) CPE ACV IC50 1 µg/mL, SI ˃ 250 | HSV-1 IC50 52.7 µg/mL, SI ˃ 9.5 | The activity may be associated with their influence on mitotic division. 113 and 114 are included for comparison of effect (non-terpenoid compounds) | [68] | |
Andrographolide (82) | Vero cells, HSV-1 PRA ACV IC50 < 1 µg/mL | IC50 8.28 µg/mL | Ent-labdane diterpenes Andrographis paniculata No cytotoxic effect at virucidal concentration. | [69] | |
Neoandrographolide (83) | IC50 7.97 µg/mL | ||||
14-deoxy-11,12-didehydroandrographolide (84) | IC50 11.1 µg/mL | ||||
10,18-diacetoxy-8-hydroxy-2, 6-dolabelladiene (85) | Vero cells, HSV-1 CPE ACV at 15 µM, 79% of CPE | At 50 µM, 89% of CPE | Dollabene diterpenes brown alga Dictyota pfaffi Effect on HIV-1 reverse transcriptase. | [70] | |
10-acetoxy-8,18-di-hydroxy-2,6-dolabelladiene (86) | At 50 µM, 87% of CPE | ||||
Steroids | Fomitopsin D (87) | Vero cells, HSV-1 Green fluorescent protein (GFP) expression ACV IC50 2.18 μg/mL | HSV-1 IC50 17 μg/mL | Steroid Fungus Fomitopsis | [71] |
Lyonifoloside A (88) | Vero cells, HSV-1 (F strain VR 733) CPE ACV EC50 0.41 μM, SI > 244 | EC50 11.1 μM, SI = 2.1 | 9,10-seco-cycloartanes 88–90, lanosterol derivatives 91–93 Lyonia ovalifolia | [72] | |
Lyonifolic acid A (89) | EC50 3.7 μM, SI = 4.3 | ||||
Lyofoligenic acid (90) | EC50 11.1 μM, SI = 5.2 | ||||
Lyonifolic acid C (91) | EC50 2.1 μM, SI = 7.6 | ||||
Lyonifoloside M (92) | EC50 6.4 μM, SI = 3.0 | ||||
Lyonifoloside P (93) | EC50 14.3 μM, SI > 7.0 | ||||
Cucurbitacin B (94) | Vero cells, HSV-1 (KOS) PRA Acyclovir IC50 1.74 μM, SI > 132.2 | IC50 0.94 μM, SI = 127.7 | Cucurbitane steroid Cucurbitaceae | [73] | |
TSH (halistanol (95) rich fraction) | Vero cells, HSV-1 (KOS) PRA Effects on HSV-1 attachment and penetration ACV IC50 3.45 ± 0.42 μg/mL, SI > 580 | IC50 2.87 ± 0.78 μg/mL, SI = 15.53 | Brazilian marine sponge Petromica citrina (Demospongiae) The observed anti-HSV-1 activity was found to be mediated by the inhibition of virus attachment and by the penetration into Vero cells, the virucidal effect on virus particles, and by the impairment in levels of ICP27 and gD proteins of HSV-1. Synergic effect with acyclovir | [74] | |
Halistanol sulfate (96) | IC50 5.63 ± 1.37 μg/mL, SI = 2.46 | ||||
Halistanol sulfate C (97) | IC50 6.09 ± 1.51 μg/mL, SI = 1.95 | ||||
Pentacyclic triterpenes | Glycyrrhizic acid (98) | HeLa cells, HSV-1 CPE | At 1 and 2 mM, the inhibition ranged from about 78% to 85% | Oleanane triterpene Glycyrrhizha spp. 24h pre-treatment strongly enhanced the antiviral activity of 98 (at 2 mM), with a viral inhibition that rise as high as 95%–98%. 98 is a strong inducer of the autophagy activator Beclin 1 (connected to resistance to HSV-1 infection). | [75] |
Glycyrrhetic acid (101) and its methylester (102) | Vero cells, HSV-1 strain (KOS) PRA ACV IC50 1.1 ± 0.09 µM, SI> 400 | IC50 21.7 ± 0.06 and 8.1 ± 0.2 µM, respectively. SI = 3.9 and > 26, respectively. | Oleanane triterpene Glycyrrhiza spp. The hydroxylation at C-21 seems to be responsible for the reduction of anti-HSV-1 activity, the C-29 hydroxy group would eliminate the anti-HSV-1 activity. C-20 methoxy or carboxy groups should be responsible for the enhancement of activity. | [76] | |
3α-hydroxylup-20(29)-ene-23,28-dioic acid (99) | Vero cells, HSV-1 (15577) CPE ACV IC50 0.25 µg/mL, SI > 2000 | IC50 31.3 µg/mL, SI = 3.8 | Lupane triterpenes Schefflera heptaphylla Other viruses tested | [77] | |
3-epi-betulinic acid 3-O-sulphate (100) | IC50 20 µg/mL, SI = 5 | ||||
Oleanolic acid (103) | Vero cells, HSV-1 (strain F), HSV-2 (strain G) CPE Viral inactivation or virucidal assay Viral penetration assay Time response assay Amplification of viral DNA by PCR ACV HSV-1 EC50 2.1 ± 0.1 μg/mL, SI = 61.9; HSV-2 EC50 2.9 ± 0.1 μg/mL, SI = 44.8 | HSV-1 EC50 6.8 ± 1.24 μg/mL, SI = 14.4 HSV-2 EC50 7.8 ± 1.4 μg/mL, SI = 12.6 | Common oleanane triterpene Possible inhibition of the early stage of HSV multiplication | [78] | |
Asprellanoside A (104) | Vero cells, HSV-1 PRA ACV total inhibitory concentration (TIC) 0.0043 mM | TIC 0.14 mM | Sulphur containing triterpenoid saponins Ilex asprella | [79] | |
Oblonganoside H (105) | TIC 0.18 mM | ||||
Tereticornate (106) | Vero cells, HSV-1 (KOS), HSV-2 (clinical isolates) PRA, TRI ACV HSV-1 IC50 1.92 ± 0.23 μg/mL, SI >109.4, HSV-2 IC50 1.75 ± 0.33, SI > 120.0 | HSV-1 IC50 0.96 ± 0.12, SI > 218.8 | 106 - triterpene Eucalyptus globulus | [58] | |
3β-O-trans-ferulyl-20-hydroxy-lup-28-oic acid (107) | Vero cells, HSV-1 (F strain VR 733) CPE inhibition method ACV IC50 0.41 ± 0.3 µM, SI > 243.9 | IC50 0.71 ± 0.06, SI 5.2 | Triterpene Rhododendron latoucheae | [80] |
Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source |
---|---|---|---|---|
Trichobotrysin A (108) | Vero cells, HSV-1 PRA ACV IC50 3.50 μM | IC50 3.08 μM | Deep-sea-derived fungus Trichobotrys effuse Tetramic acid derivatives | [81] |
Trichobotrysin B (109) | IC50 9.37 μM | |||
Trichobotrysin D (110) | IC50 3.12 μM | |||
(E)-2-(2,4-hexa-diynyliden)-1,6-dioxaspiro[4.5] dec-3-ene (111) | Vero cells, HSV-1 (clinical isolate with >99% homology to isolate SK087 US4–6 genes), HSV-2 (clinical isolate >99% homology to isolate 99-62039 US4 gene) CPE, YRA Time-of-addition, adsorption inhibition, virucidal, penetration inhibition assays Macromolecular synthesis inhibition analysis ACV HSV-1 EC50 0.9 μg/mL; SI > 1000 / HSV-2 EC50 0.7 μg/mL; SI > 1000 | EC50, SI: HSV-1/HSV-2 0.146 μg/mL; > 205 / 0.127 μg/mL; > 236 | Tanacetum vulgare Spiroketal-enol ether derivative. Mechanism of antiviral activity elucidated on petroleum ether extract and 111 (inhibition of viral gene expression). | [82] |
Monogalactosyl diglyceride (112) and digalactosyl diglyceride (DGDG) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 IC50 0.64 μg/mL and HSV-2 IC50 0.80 μg/mL | HSV-1 IC50 36.00 μg/mL for 112 and 40.00 μg/mL for DGDG, respectively. HSV-2 IC50 41.00 μg/mL for 112 and 43.20 μg/mL for DGDG, respectively. | Clinacanthus nutans | [83] |
Methyl (N-benzoyl-(2′R,3′S)-3′-phenylisoserinate) (113) | Vero cells, HSV-1 (MacIntyre strain) CPE ACV IC50 1 µg/mL, SI ˃ 250 | HSV-1 IC50 10.7 µg/mL, SI ˃ 46.7 | Taxol derivatives. The activity may be associated with their influence on mitotic division. | [68] |
N-benzoyl-(2′R,3′S)-3′-phenylisoserine (114) | HSV-1 IC50 21.7 µg/mL, SI ˃ 23 |
Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source |
---|---|---|---|---|
PSP-B2 polysaccharide from Prunellae Spica (Prunella vulgaris L.) | Vero cells, HSV-1, HSV-2 PRA ACV HSV-1 IC50 0.78 µM, HSV-2 1.32 μM | HSV-1 IC50 69 μg/mL HSV-2 IC50 49 μg/mL | No cytotoxicity even at 1600 μg/mL | [84] |
Eucheuma gelatinae (seaweed) polysaccharide | Vero cells, HSV-1 PRA ACV EC50 HSV-1(strain F), HSV-2 (strain 333), HSV-1 (strain 106), HSV-1 (strain 153), and HSV-1 (strain blue) 0.78, 0.71, 9.60, 21.11, and 23.50 μg/mL, respectively | HSV-1/F, HSV-2/333, HSV-1/106, HSV-1/153, and HSV-1/blue EC50 0.65, 2.12, 1.11, 1.24, and 1.48 μg/mL, respectively | Effect via activity on early HSV-1 infection. Inhibition of viral DNA synthesis. | [85] |
Sulfated polysaccharide SP-III from Sargassum latifolium | Vero cells, HSV-1 PRA | SP-III 33% and 81% inhibition at 20 μg/mL and 40 μg/mL, respectively. | Glucuronic acid, mannose, glucose, xylose and fucose. | [86] |
Sulfated polysaccharide SP-2a from Sargassum patens (Kütz.) Agardh | Vero cells, HSV-1 (15577 strain, clinical strain, DM2.1 strain-ACV resistant) PRA Determination of extracellular virucidal activity Time of addition experiment Virus adsorption assay | Inhibition of replication of both the acyclovir-sensitive and -resistant strains of HSV-1, in a dose-dependent manner, EC50 1.5–5.3 μg/mL | Fucose, xylose, mannose, glucose, galactose, galactosamine Extracellular virucidal activity only against the ACV-sensitive strains. This compound might inhibit the attachment of the virus to its host cell. | [87] |
ST-F polysaccharide from marine brown algae Sargassum trichophyllum | Vero cells, HSV-2 (UW264 strain) PRA Time of addition experiment | Added to the medium during infection and throughout the incubation (Experiment A) or immediately after viral infection (Experiment B), IC50 18 and 410 μg/mL, respectively. SI > 280 and >12 for A and B, respectively. | (Fucose and galactose) The main antiviral target of ST-F might be virus adsorption and/or penetration step(s) on the host cell surface. Low cytotoxicity | [88] |
SPs - sulfated polysaccharides from brown sea algae Sargassum fluitans and red sea algae Solieria filiformis | Vero cells, HSV-1 Neutral red dye method ACV EC50 15.4 ± 5.6 μg/mL | S. fluitans EC50 42.8 ± 4.3 μg/mL and S. filiformis EC50 136.0 ± 12 μg/mL Without cytotoxicity (1–200 μg/mL) | The activity observed suggests that the degree of sulfation, molecular weight, and carbohydrate nature of these polysaccharides may affect the activity | [89] |
Polysaccharide fractions C1p and C4p from chlorophyta Ulva armoricana | Vero cells, HSV-1 (wild-type strain 17, sensitive to ACV) CPE ACV EC50 0.3 µg/mL | EC50 373.0 ± 20.7 and 320.9 ± 6 µg/mL | Activities correlated to amounts of rhamnose, uronic acids and degree of sulfation. | [90] |
Sp-Am polysaccharide from Acanthophora muscoides | Vero cells, HSV-1, HSV-2 CPE | HSV-1 IC50 1.63 μg/mL, SI = 3.5 HSV-2 IC50 3.5 μg/mL, SI = 99.9 | Sulfated polysaccharides from marine seaweeds The possible mechanism of the effect - the inhibition of virus adsorption. | [91] |
SP-Gb polysaccharide from Gracila riabirdiae | HSV-1 IC50 0.75 μg/mL, SI = 1.25 HSV-2 IC50 82.2 μg/mL, SI = 94.40 | |||
SP-Sf polysaccharide from Solieria filiformis | HSV-1 IC50 0.6 μg/mL, SI = 1.6 HSV-2 IC50 74.9 μg/mL, SI = 97.5 | |||
PSC polysaccharide from marine seaweed Sphaerococcus coronopifolius | Vero cells, HSV-1 (wild type strain 17, sensitive to ACV) CPE Time of addition assay Virus adsorption assay ACV SI ˃ 500 | EC50 4.1 μg/mL, SI = 61 | Galactose, 3,6-anhydrogalactose, uronic acids, sulfated The adsorption step of HSV-1 to the host cell possible mechanism of action. | [92] |
PBT polysaccharide from marine seaweed Boergeseniella thuyoides | EC50 17.2 μg/mL, SI = 14.5 | |||
Sulfated xylogalactofucans and alginic acids from brown algae Laminaria angustata | RC-37 cells, HSV-1 (KOS) PRA Time of addition assay Virus adsorption assay Virucidal assay | IC50 0.21–25 μg/mL, SI ˃ 40 ˃ 3225 | Possible inhibiting HSV attachment to cells by direct interaction with viral particles. | [93] |
SU1F1 polysaccharide from green algae Enteromorpha compressa | HEp-2 cells, HSV-1 (clinical isolate) PRA Time-of-addition assay Inhibition of adsorption assay Inhibition of penetration assay Virucidal assay Acyclovir IC50 2100 μg/mL, SI = 1.21 | IC50 28.25 μg/mL, SI = 35.3 | Chemically altered- sulfated ulvan Broad mechanism of action. | [94] |
Sulfated fucoidans (S1-S3) from marine brown alga Padina tetrastomatica | Vero cells, HSV-1 (strains F and B2006), HSV-2 (strain MS) PRA Virucidal assay Effect of treatment period on the antiviral activity | HSV-1 and HSV-2 with IC50 in range of 0.30–1.05 μg/mL B2006 S3 IC50 0.6 μg/mL | Active during the virus adsorption period Degree of sulfation affects the activity | [95] |
Polysaccharides from brown seaweed Stoechospermum marginatum | Vero cells, HSV-1 (strains F, TK- B2006 and filed strains, syncytial variants arising after selection with a natural carrageenan, syn 13-8 and 14-1), HSV-2 (MS) PRA | HSV-1 (F) EC50 1.15-50 μg/mL, SI = ˃20 ˃ 869 HSV-2 (MS) EC50 0.78 μg/mL, SI= 0.57 ˃50 F3 B2006, Field, 13-8 and 14-1 strains EC50 0.95, 1.52, 4.52 μg/mL, SI ˃1053, ˃658, ˃221, ˃176 | Sulfated fucans Active during the virus adsorption period. No direct virucidal activity. No correlation between the antiviral and anticoagulant activity. | [96] |
CiWE CiF3 polysaccharides from brown seaweed Cystoseira indica | Vero cells, HSV-1 (strain F), HSV-2 (strain MS) PRA | IC50 values in the range of 0.5–2.8 μg/mL | Sulfated fucans Degree of sulfation affects the activity. No correlation between the antiviral and anticoagulant activity. | [97] |
Sulfated polysaccharide (fucoidan) from brown algae Undaria pinnatifida (Mekabu) | Vero cells, HSV-1 (strain HF), HSV-2 (strain UW-268) PRA A) 1 h after the viral infection, B) immediately after infection | HSV-1 IC50 and SI A) 2.5 μg/mL, ˃800; B) 14 μg/mL, ˃140 HSV-2 IC50 and SI A) 2.6 μg/mL, ˃770; B) 5.1 μg/mL, ˃390 | Fucose, galactose Other viruses tested. | [98] |
Polysaccharides (GiWE and F3) from red seaweed Grateloupia indica | Vero cells, HSV-1 (strain F, TK- B2006 and filed strains, syncytial variants arising after selection with natural carrageenan, syn 13-8 and 14-1), HSV-2 (MS) PRA | HSV-1 (F) IC50 0.27 μg/mL and HSV-2 (MS), IC50 0.31 μg/mL F3 B2006, Field, 13-8 and 14-1 strains EC50 0.89, 0.87, 1.06, 0.81 μg/mL, SI ˃ 1123, ˃1149, ˃943, ˃1234 No direct virucidal activity at 40 μg/mL | Sulfated galactans Degree of sulfation affects the activity. Possible ability to interfere with the replication cycle. | [99] |
Polysaccharide from Schizymenia binderi | Vero cells, HSV-1 (strains F, TK− (B2006), (Field)), HSV-2 (G) PRA | EC50 0.21-0.76 μg/mL SI > 1000 for all assays No cytotoxicity at 1000 μg/mL | Sulfated galactan Interference with the initial adsorption of viruses to cells, no virucidal activity at 100 μg/mL. | [100] |
Polysaccharide from red seaweed Gigartina skottsbergii | Vero cells, HSV-1 (strains F, TK− (B2006), (Field), clinical isolates 1213 LCR/94, 374 LCR/94 and 1180 BE/94), HSV-2 (G, clinical isolate 244 BE/94) PRA | 1C3 HSV-1 (F) and HSV-2 (G) EC50 0.7 and 0.5 µg/mL, respectively, SI ˃ 1408 and ˃2128 1T1 HSV-1 (F) and HSV-2 (G) EC50 0.6 and 0.4 µg/mL, respectively, SI ˃ 1538 and ˃2439 Clinical isolates EC50 0.19–2.18 µg/mL | Carrageenans Lack of anticoagulant activity No virucidal activity, effect on virus adsorption | [101] |
Proteoglycan GLPG from Ganoderma lucidum (Agaromycetes)—lingzhi mushroom | Vero cells, HSV-1, HSV-2 CPE Virus yield inhibition assay | HSV-1 and HSV-2 EC50 48 and 56 µg/mL, respectively, SI ˃ 42 and >36 No cytotoxicity at 2000 µg/mL | Proteoglycan GLPG (carbohydrate: protein ratio of 10.4: 1) The antiviral activity may be due to its inhibiting HSV attachment to cells, in addition, its inhibition of viral penetration would augment its antiviral activity. | [102] |
Polysaccharide RP from Portulaca oleracea | Vero cells, HSV-2 (UW268 strain) PRA Time-of-addition assay Virus adsorption and penetration assay | A: RP added during infection and throughout the incubation thereafter B: RP added immediately after viral infection. A: EC50 210 µg/mL, SI = 33 B: EC50 320 µg/mL, SI = 22 | Pectic polysaccharide (RP) Activity against influenza virus tested on MDCK cells. | [103] |
Polysaccharide SPLCf from Caesalpinia ferrera | HEp-2 cells, HSV-1 (clinical isolate) PRA Time-of-addition assay Inhibition of adsorption assay Inhibition of penetration Virucidal activity HSV-1 cell to cell spread assay ACV IC50 2100 μg/mL, SI >1.21 | IC50 405 μg/mL, SI > 7.4. | Sulfated polysaccharide SPLCf showed the effect on several stages of the HSV replication—virus adsorption, the effect on virus particles and the expression of viral protein. | [104] |
Polysaccharides (ANP, AAP) from Acanthopanax sciadophylloides | Vero cells, HSV-2 (UW264 strain) PRA In vivo anti-HSV-2 effects on female BALB/c mice ACV In vivo: Polysaccharides (1 mg/20 μL) or ACV (0.2 mg/20 μL) administered intravaginally twice per day from 3 days before infection to 7 days post-infection. | ANP and AAP IC50 52 and 620 μg/mL when added to the medium during infection and throughout the incubation thereafter HSV-2 IC50 67 and 580 μg/mL when added to the medium immediately after infection. | Acanthopanax sciadophylloides Virus titers in the vaginal region were decreased by the administration of AAP. | [105] |
Acidic polysaccharide (nostoflan) from terrestrial cyanobacterium Nostoc flagelliforme | Vero cells, HSV-1 (HF strain) and HSV-2 (UW268 strain) PRA | A: added during infection and throughout the incubation thereafter B: added immediately after viral infection A: HSV-1 IC50 0.37 μg/mL, SI = 13000 A: HSV-2 IC50 2.9 μg/mL, SI = 2700 B: HSV-1 IC50 ˃100 μg/mL, SI = <49 B: HSV-2 IC50 7.7 μg/mL, SI = 1000 | Other antiviral activity tested. No anti-thrombin activity. | [106] |
Polysaccharide sulfate fraction from Caulerpa racemosa | Vero cells, HSV-1 strain F, TK- B2006 and field strains), HSV-2 G strain) PRA | HSV-1 (strain F, TK- B2006 and field strains) EC50 4.2, 2.4, 2.2 µg/mL, SI ˃ 238, ˃417, ˃454 HSV-2 (strain G) EC50 3.0 µg/mL, SI ˃ 333 No cytotoxic effects up to 1000 µg/mL | Galactose, glucose, arabinose, and xylose as the major components. | [107] |
Compound | Antiherpetic and Cytotoxicity Assays, Strains, Cells, and Reference Agents | Results | Additional Information | Source |
---|---|---|---|---|
Bacteriocins (semi-purified) | Vero cells, HSV-1 (strain EK) CPE Viral adsorption assay | Before adsorption IC50 235.6 μg/mL, SI 4.6 (for GEn14) After adsorption IC50 24.0 μg/mL, SI 17.8 (for GEn17) | Bacteria from goat milk Enterococcus durans (GEn09, GEn12, GEn14, and GEn17). | [108] |
Subtilosin | Vero cells, HSV-2 (strain G) PRA Virucidal assay Time-of-addition assay Indirect immunofluorescence assay | At 200 μg/mL a reduction over 99.9% in virus titer EC50 18.2 μg/mL, SI 17.4 | Bacillus amyloliquefaciens Cyclic peptide Antiviral and virucidal effect. This compound affects late stages of the viral replicative cycle such as viral glycoprotein intracellular transport. | [109] |
Simplicilliumtide J | Vero cells, HSV-1 PRA ACV IC50 3.0 µM | IC50 14.0 µM | Deep-Sea-Derived Fungus Simplicillium obclavatum Cyclic peptides | [110] |
Verlamelin A | IC50 16.7 µM | |||
Verlamelin B | IC50 15.6 µM | |||
Aspergillipeptide D | Vero cells, HSV-1 (strain 15577, ACV resistant clinical isolates HSV-1-106 and HSV-1-153) CPE ACV IC50 3 µM | HSV-1 (strain 15577) IC50 9.5 µM | Marine gorgonian-derived fungus Aspergillus sp. No cytotoxicity at concentrations tested. Aspergillipeptide D showed activity against acyclovir-resistant HSV-1-106 and HSV-1-153. | [111] |
Aspergillipeptide E | HSV-1 (strain 15577) IC50 19.8 µM | |||
RC28 (28.25 kDa) protein | BGMK cells, HSV-1 (KOS) CPE | IC50 0.078 mg/mL, SI > 32 | Edible mushroom Rozites caperata (Cortinarious caperata) | [112] |
Pa-MAP | Vero cells, HSV-1 Virus titer reduction method Virucidal assay ACV at 20 μg/mL PI 99% | EC50 83 μg/mL, SI ˃ 5 | Polar fish Pleuronectes americanus | [113] |
Bovine lactoperoxidase | Vero cells, HSV-1 PRA | At 0.5 mg/mL 100% antiviral effect | Milk hemoprotein | [114] |
Griffithsin | Vero cells, HeLa cells, HSV-2 (strain G) PrestoBlue cell viability reagent - reading of fluorescence Flow cytometry Inhibition of adsorption assay In vivo HSV-2 murine model | EC50 5.8 μg/mL (230 nM) Griffithsin/carrageenan combination EC50 3.4 ng/mL | Red alga Griffithsia A lectin with high affinity for mannose-rich N-linked glycans. Griffithsin may block viral entry by binding to HSV-2 glycoprotein D. The griffithsin/carrageenan combination product but not GRFT or CG alone, reduced HSV-2 vaginal infection in mice when given an hour before challenge. | [115] |
Melittin | Vero cells, HSV-1 Virus yield inhibition assay | EC50 1.35 μM; SI 6.3 | Cationic 26 amino acids peptide isolated from insects—the main component of bee venom | [116] |
Chemical Class | Compound | Mechanisms of Action or Types of Inhibition | Structure–Activity Relationship (SAR) |
---|---|---|---|
Flavan-3-ol (flavonoid) | Epicatechin gallate (ECG) (8) | Inhibition of viral adsorption. | — |
Flavonol (flavonoid) | Galangin (11) | Inhibition of viral adsorption. | — |
Flavonol (flavonoid) | Quercetin (19) | Inhibition of the expressions of HSV proteins (gD, ICP0) and genes (ICP0, UL13, UL52). Additionally, this molecule suppressed the expression of TLR-3 and inhibited the transcriptional factors NF-κB and IRF3. | — |
Flavonoid | Houttuynoid A (21) | Blocking viral membrane fusion. | — |
Phenolics | kuwanon C (22), kuwanon T (23), kuwanon U (24), kuwanon E (25), and ethyl 2,4-dihydroxybenzoate (37) | Inhibition of HSV-1 and HSV-2 replication (in vitro) and inactivation of HSV-1 DNA polymerase and HSV-2 protease (proposed as competitive inhibitors via in silico assay). | Hydroxyl, carbonyl, and methyl groups along with phenyl ring (proposed as functional groups via in silico assays). |
Alkyl derivatives of gallic acid | Octyl gallate (39) | Inhibition of multiplication of HSV-1 and suppression of formation of virus progeny at early stages (within 6 h post-infection) in the infected cells. | Alkyl moieties. |
Tannins | Chebulagic acid (40) and chebulinic acid (41) | Avoiding the attachment and penetration of HSV-2 into Vero cells. | — |
β-orcinol depsidone, a type of phenolic compound | Psoromic acid (45) | Inhibition of HSV-1 and HSV-2 replication and inactivation of HSV-1 DNA polymerase (competitive inhibitor via in vitro and in silico experiments). Also, via in silico assay, inactivates HSV-2 protease (competitive inhibitor). | Hydroxyl, carbonyl, and methyl groups along with phenyl ring (proposed as functional groups via in silico assays). |
Stilbene derivative | Kuwanon X (51) | Anti-HSV activity through multiple modes of action (impeded cellular adsorption and penetration of HSV-1 viral particles). After viral penetration, this agent decreased the expression of HSV-1 IE and L genes and diminished the synthesis of HSV-1 DNA. Moreover, this molecule prevented the HSV-1-induced nuclear factor (NF)-κB activation via obstructing the nuclear translocation and DNA binding of NF-κB. | — |
Flavonoid | Curcumin (56) | Inhibition of adsorption and replication of HSV. | Hydroxyl groups (assessed as functional groups). |
Alkaloid | Harmine (59) | Inhibition of viral protein expression. | — |
Monoterpenoid | Geraniol (62) | Inhibition of HSV-2 replication (in vitro assay) and inactivation of HSV-2 protease (in silico assay). | Hydroxyl and methyl groups (proposed as functional groups via in silico assay). |
Steroids | Halistanol sulfate (96) and halistanol sulfate C (97) | Suppression of HSV-1 attachment and penetration into the host cells. These substances also impair the levels of ICP27 and gD proteins of HSV-1. | Sulfate groups (assessed as functional groups). |
Triterpene glycoside | Glycyrrhizic acid (98) | The compound was detected to be an effective inducer of the autophagy activator Beclin 1, which creates a resistance to HSV-1 replication. | Carboxyl and hydroxyl groups along with sugar moiety (assessed as functional groups). |
Triterpenoid | Methylester of glycyrrhetic acid (102) | Inhibition of HSV-1 replication. | Methoxy and carboxy groups at C-20 were noted to be responsible for the enhanced inhibitory activity against HSV-1 replication. |
Pentacyclic triterpenoid | Oleanolic acid (103) | Inhibition of HSV-1 and HSV-2 multiplication at the early stage. | — |
Spiroketal-enol ether derivative | (E)-2-(2,4-hexa-diynyliden)-1,6-dioxaspiro[4.5] dec-3-ene (111) | Suppression of viral gene expression and reduction of viral protein accumulation within infected cells. | — |
Taxol derivatives | Methyl (N-benzoyl-(2′R,3′S)-3′-phenylisoserinate) (113) and N-benzoyl-(2′R,3′S)-3′-phenylisoserine (114) | Inhibition of HSV-1 replication (the inhibitory activity might be related to the impact on the mitotic division). | — |
Polysaccharides | Polysaccharides and sulfated polysaccharides | Multiple mechanisms of action (inhibition of HSV replication, inhibition of virus adsorption, suppression of gene expression, suppression of HSV attachment and penetration into the host cell). | Sugar moieties and sulfate groups. |
Cyclic peptide | Subtilosin | This antiherpetic agent alters the late stages of the viral replicative cycle such as viral glycoprotein intracellular transport. | — |
Peptide | Griffithsin | Blocking viral entry by attaching with HSV-2 glycoprotein D. | — |
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Treml, J.; Gazdová, M.; Šmejkal, K.; Šudomová, M.; Kubatka, P.; Hassan, S.T.S. Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development. Viruses 2020, 12, 154. https://doi.org/10.3390/v12020154
Treml J, Gazdová M, Šmejkal K, Šudomová M, Kubatka P, Hassan STS. Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development. Viruses. 2020; 12(2):154. https://doi.org/10.3390/v12020154
Chicago/Turabian StyleTreml, Jakub, Markéta Gazdová, Karel Šmejkal, Miroslava Šudomová, Peter Kubatka, and Sherif T. S. Hassan. 2020. "Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development" Viruses 12, no. 2: 154. https://doi.org/10.3390/v12020154
APA StyleTreml, J., Gazdová, M., Šmejkal, K., Šudomová, M., Kubatka, P., & Hassan, S. T. S. (2020). Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development. Viruses, 12(2), 154. https://doi.org/10.3390/v12020154