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The hepatitis virus is one of the major burdens on the global health system. There are currently numerous types of hepatitis virus, with both known and unknown etiologies. Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the most prevalent infectious agents linked to chronic liver disease, including hepatocellular carcinoma and cirrhosis. In healthcare facilities, the use of contaminated blood poses a risk; the infection can be transmitted through unsafe injection practices, the injection of drugs, the transfusion of unscreened blood, and sexual practices involving blood inflammation.
- Anti-Hepatitis Virus
- Microbial Natural Products
- HBV
- HCV
1. Anti-Hepatitis C Virus
Chronic Hepatitis C virus (HCV)V infection affects approximately 71 million people, and approximately 400,000 people have died due to the infection, with 3–4 million new infections occurring each year [1][52]. Antiviral medications have been shown to cure approximately 95% of people infected with hepatitis C. The mechanism of action varies, but it involves the inhibition of viral-derived proteins, such as non-structural protein (NS)5A [2][53], NS5B [3][54], and NS3/4A [4][55]. Several direct acting antiviral drugs are currently available to combat HCV, including NS3/4A inhibitors (paritaprevir, asunaprevir, simeprevir, telaprevir, grazoprevir, and boceprevir), NS5A inhibitors (ledipasvir, ombitasvir, elbasvir, daclatasvir, and velpatasvir), and NS5B inhibitors (dasabuvir and sofosbuvir) [5][56]. However, these therapeutic drugs have some side effects and are quite expensive.
As shown in Table 1, a number of natural products produced by microorganisms have the potential to be developed into anti-hepatitis B virus (HBV) medications. It is widely believed that fungi represent one of the most promising sources of bioactive compounds from which anti-HBV drugs could be developed. In 1977, Marchelli and her colleagues purified for the first time a didehydropeptide, which was given the name NeoB. It is an abbreviation for neoechinulin B, which was isolated from the fungus Aspergillus amstelodami [6][57]. Nakajima and his colleagues later demonstrated that NeoB inhibited the development of infectious HCV in Huh-7 cells [7][58]. By inhibiting the liver X receptors (LXRs), its molecule improved the efficacy of all known anti-HCV drugs and demonstrated a significant synergistic effect when combined with either an HCV NS5A inhibitor or interferon [7][58]. To achieve high yields, Nishiuchi and his colleagues also developed the synthetic antiviral agent NeoB and other derivatives [8][20].
Table 1.
Natural product produce by microbes and its target.
| Compound Name [Ref.] | Compound Type | Microbial Strain | Strain Origin/Host | Viral Target | IC | 50 | /EC | 50 | /ED | 50 | Target Inhibition | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| alachalasin A [9] | alachalasin A [25] | alkaloid | Podospora vesticola | XJ03-56-1 | glacier | HIV-1 | EC | 50 | = 8.01 μM | ND | ||
| pestalofone A [10] | pestalofone A [28] | terpenoid | Pestalotiopsis fici | W106-1 | plant endophyte | HIV-1 | EC | 50 | = 90.4 μM | ND | ||
| pestalofone B [10] | pestalofone B [28] | terpenoid | P. fici | W106-1 | plant endophyte | HIV-1 | EC | 50 | = 64.0 μM | ND | ||
| pestalofone E [10] | pestalofone E [28] | terpenoid | P. fici | W106-2 | plant endophyte | HIV-1 | EC | 50 | = 93.7 μM | ND | ||
| pestaloficiol G [10] | pestaloficiol G [28] | terpenoid | P. fici | W106-3 | plant endophyte | HIV-1 | EC | 50 | = 89.2 μM | ND | ||
| pestaloficiol H [10] | pestaloficiol H [28] | terpenoid | P. fici | W106-4 | plant endophyte | HIV-1 | EC | 50 | = 89.2 μM | ND | ||
| pestaloficiol J [10] | pestaloficiol J [28] | terpenoid | P. fici | W106-5 | plant endophyte | HIV-1 | EC | 50 | = 8 μM | ND | ||
| pestaloficiol K [10] | pestaloficiol K [28] | terpenoid | P. fici | W106-6 | plant endophyte | HIV-1 | EC | 50 | = 78.2 μM | ND | ||
| epicoccin G [11] | epicoccin G [95] | alkaloid | Epicoccum nigrum | XZC04-CS-302 | Cordyceps sinensis | fungus | HIV-1 | EC | 50 | = 13.5 μM | ND | |
| epicoccin H [11] | epicoccin H [95] | alkaloid | E. nigrum | XZC04-CS-302 | C. sinensis | HIV-1 | EC | 50 | = 42.2 μM | ND | ||
| diphenylalazine A [11] | diphenylalazine A [95] | peptide | E. nigrum | XZC04-CS-302 | C. sinensis | HIV-1 | EC | 50 | = 27.9 μM | ND | ||
| bacillamide B [12] | bacillamide B [30] | peptide | Tricladium sp. | No. 2520 | soil in which | C. sinensis | grow | HIV-1 | EC | 50 | = 24.8 μM | ND |
| armochaetoglobin K [13] | armochaetoglobin K [31] | alkaloid | Chaetomium globosum | TW 1-1 | Armadillidium vulgare | insect | HIV-1 | EC | 50 | = 1.23 μM | ND | |
| armochaetoglobin L [13] | armochaetoglobin L [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.48 μM | ND | |
| armochaetoglobin M [13] | armochaetoglobin M [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.55μM | ND | |
| armochaetoglobin N [13] | armochaetoglobin N [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.25 μM | ND | |
| armochaetoglobin O [13] | armochaetoglobin O [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.61 μM | ND | |
| armochaetoglobin P [13] | armochaetoglobin P [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.68 μM | ND | |
| armochaetoglobin Q [13] | armochaetoglobin Q [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.31 μM | ND | |
| armochaetoglobin R [13] | armochaetoglobin R [31] | alkaloid | C. globosum | TW 1-1 | A. vulgare | insect | HIV-1 | EC | 50 | = 0.34 μM | ND | |
| stachybotrin D [14] | stachybotrin D [32] | terpenoid | Stachybotrys chartarum | MXH-X73 | Xestospongia testudinaris | sponge | HIV-1 | EC | 50 | = 8.4 μM | replication | |
| stachybotrysam A [15] | stachybotrysam A [33] | alkaloid | S. chartarum | CGMCC 3.5365. | ND | HIV-1 | EC | 50 | = 9.3 μM | ND | ||
| stachybotrysam B [15] | stachybotrysam B [33] | alkaloid | S. chartarum | CGMCC 3.5365. | ND | HIV-1 | EC | 50 | = 1.0 μM | ND | ||
| stachybotrysam C [15] | stachybotrysam C [33] | alkaloid | S. chartarum | CGMCC 3.5365. | ND | HIV-1 | EC | 50 | = 9.6 μM | ND | ||
| chartarutine B [16] | chartarutine B [34] | alkaloid | S. chartarum | WGC-25C-6 | Niphates | sp. sponge | HIV-1 | IC | 50 | = 4.90 μM | ND | |
| chartarutine G [16] | chartarutine G [34] | alkaloid | S. chartarum | WGC-25C-6 | Niphates | sp. sponge | HIV-1 | IC | 50 | = 5.57 μM | ND | |
| chartarutine H [16] | chartarutine H [34] | alkaloid | S. chartarum | WGC-25C-6 | Niphates | sp. sponge | HIV-1 | IC | 50 | = 5.58 μM | ND | |
| malformin C [17] | malformin C [35] | peptide | Aspergillus niger | SCSIO Jcsw6F30 | marine | HIV-1 | IC | 50 | = 1.4 μM | entry | ||
| aspernigrin C [18] | aspernigrin C [181] | alkaloid | A. niger | SCSIO Jcsw6F30 | marine | HIV-1 | IC | 50 | = 4.7 μM | entry | ||
| eutypellazine E [19] | eutypellazine E [36] | alkaloid | Eutypella | sp. MCCC 3A00281 | deep sea sediment | HIV-1 | IC | 50 | = 3.2 μM | ND | ||
| truncateol O [20] | truncateol O [37] | terpenoid | Truncatella angustata | XSB-01-43 | Amphimedon | sp. sponge | HIV-1 and H1N1 | IC | 50 | = 39.0 μM (HIV) and 30.4 μM (H1N1) | ND | |
| truncateol P [20] | truncateol P [37] | terpenoid | T. angustata | XSB-01-43 | Amphimedon | sp. sponge | HIV-1 | IC | 50 | = 16.1 μM | ND | |
| penicillixanthone A [21] | penicillixanthone A [38] | polyketide | Aspergillus fumigatus | jellyfish | HIV-1 | IC | 50 | = 0.26 μM | entry | |||
| DTM [22] | DTM [39] | polyketide | C. globosum | deep sea sediment | HIV-1 | 75.1% at 20 μg/mL | ND | |||||
| epicoccone B [22] | epicoccone B [39] | polyketide | C. globosum | deep sea sediment | HIV-1 | 88.4% at 20 μg/mL | ND | |||||
| xylariol [22] | xylariol [39] | polyketide | C. globosum | deep sea sediment | HIV-1 | 70.2% at 20 μg/mL | ND | |||||
| phomonaphthalenone A [23] | phomonaphthalenone A [40] | polyketide | Phomopsis sp. | HCCB04730 | Stephania japonica | -plant endophyte | HIV-1 | IC | 50 | : 11.6 μg/mL | ND | |
| bostrycoidin [23] | bostrycoidin [40] | polyketide | Phomopsis sp. | HCCB04730 | S. japonica | plant endophyte | HIV-1 | IC | 50 | : 9.4 μg/mL | ND | |
| altertoxin I [24] | altertoxin I [41] | phenalene | Alternaria tenuissima | QUE1Se | Quercus emoryi | plant endophyte | HIV-1 | IC | 50 | : 1.42 μM | ND | |
| altertoxin II [24] | altertoxin II [41] | phenalene | A. tenuissima | QUE1Se | Q. emoryi | plant endophyte | HIV-1 | IC | 50 | : 0.21 μM | ND | |
| altertoxin III [24] | altertoxin III [41] | phenalene | A. tenuissima | QUE1Se | Q. emoryi | plant endophyte | HIV-1 | IC | 50 | : 0.29 μM | ND | |
| alternariol 5-O-methyl ether [25] | alternariol 5-O-methyl ether [42] | phenolic | Colletotrichum | sp | plant endophyte | HIV-1 | EC | 50 | : 30.9 μM | replication | ||
| ergokonin A [26] | ergokonin A [43] | terpenoid | Trichoderma | sp. Xy24 | Xylocarpus granatum | plant endophyte | HIV-1 | IC | 50 | : 22.3 μM | ND | |
| ergokonin B [26] | ergokonin B [43] | terpenoid | Trichoderma | sp. Xy24 | X. granatum | plant endophyte | HIV-1 | IC | 50 | : 1.9 μM | ND | |
| sorrentanone [26] | sorrentanone [43] | terpenoid | Trichoderma | sp. Xy24 | X. granatum | plant endophyte | HIV-1 | IC | 50 | : 4.7 μM | ND | |
| cerevisterol [26] | cerevisterol [43] | terpenoid | Trichoderma | sp. Xy24 | X. granatum | plant endophyte | HIV-1 | IC | 50 | : 9.3 μM | ND | |
| phomopsone B [27] | phomopsone B [44] | alkaloid | Phomopsis | sp. CGMCC 5416 | Achyranthes bidentata | plant endophyte | HIV-1 | IC | 50 | : 7.6 μmol/L | ND | |
| phomopsone C [27] | phomopsone C [44] | alkaloid | Phomopsis | sp. CGMCC 5416 | A. bidentata | plant endophyte | HIV-1 | IC | 50 | : 0.5 μmol/L | ND | |
| pericochlorosin B [28] | pericochlorosin B [45] | polyketide | Periconia | sp. F-31 | plant endophyte | HIV-1 | IC | 50 | : 2.2 μM | ND | ||
| asperphenalenone A [29] | asperphenalenone A [46] | alkaloid | Aspergillus | sp. | Kadsura longipedunculata | plant endophyte | HIV-1 | IC | 50 | : 4.5 μM | ND | |
| asperphenalenone D [29] | asperphenalenone D [46] | alkaloid | Aspergillus | sp. | K. longipedunculata | plant endophyte | HIV-1 | IC | 50 | : 2.4 μM | ND | |
| cytochalasin Z | 8 [29] | [46] | alkaloid | Aspergillus | sp. | K. longipedunculata | plant endophyte | HIV-1 | IC | 50 | : 9.2 μM | ND |
| epicocconigrone A [29] | epicocconigrone A [46] | alkaloid | Aspergillus | sp. | K. longipedunculata | plant endophyte | HIV-1 | IC | 50 | : 6.6 μM | ND | |
| neoechinulin B/NeoB [6][30][31] | neoechinulin B/NeoB [57,153,185] | alkaloid | Aspergillus amstelodami | ND | HCV and SARS-CoV-2 | IC | 50 | : 5.5 μM (HCV) and 32.9 μM (SARS-CoV-2) | replication | |||
| Eurotium rubrum F33 | marine sediment | H1N1 | IC50; 7 μM | entry | ||||||||
| raistrickindole A [32] | raistrickindole A [62] | alkaloid | Penicillium raistrickii | IMB17-034 | mangrove sediment | HCV | EC | 50 | : 5.7 μM | ND | ||
| raistrickin [32] | raistrickin [62] | alkaloid | P. raistrickii | IMB17-035 | mangrove sediment | HCV | EC | 50 | : 7.0 μM | ND | ||
| sclerotigenin [32] | sclerotigenin [62] | alkaloid | P. raistrickii | IMB17-036 | mangrove sediment | HCV | EC | 50 | : 5.8 μM | ND | ||
| harzianoic acid A [26] | harzianoic acid A [43] | terpenoid | Trichoderma harzianum | LZDX-32-08 | Xestospongia testudinaria | sponge | HCV | IC | 50 | : 5.5 μM | entry | |
| harzianoic acid B [26] | harzianoic acid B [43] | terpenoid | T. harzianum | LZDX-32-08 | X. testudinaria | sponge | HCV | IC | 50 | : 42.9 μM | entry | |
| peniciherquamide C [33] | peniciherquamide C [64] | peptide | Penicillium herquei | P14190 | seaweed | HCV | IC | 50: | 5.1 μM | ND | ||
| cyclo (L-Tyr-L-Pro) [34] | cyclo (L-Tyr-L-Pro) [65] | peptide | Aspergillus versicolor | Spongia officinalis | sponge | HCV | IC | 50 | : 8.2 μg/mL | replication | ||
| 7-dehydroxyl-zinniol [35] | 7-dehydroxyl-zinniol [76] | alkaloid | Alternia solani | Aconitum transsectum | plant endophyte | HBV | IC | 50 | : 0.38 mM | ND | ||
| THA [36] | THA [77] | polyketide | Penicillium | sp. OUCMDZ-4736 | mangrove sediment | HBV | IC | 50 | : 4.63 μM | ND | ||
| MDMX [36] | MDMX [77] | polyketide | Penicillium | sp. OUCMDZ-4736 | mangrove | sediment | HBV | IC | 50 | : 11.35 μM | ND | |
| vanitaracin A [37] | vanitaracin A [78] | polyketide | Talaromyces | sp. | sand | HBV | IC | 50 | : 10.58 μM | entry | ||
| destruxin A [38] | destruxin A [83] | peptide | Metarhizium anisopliae | var. | dcjhyium | Odontoternes formosanus | termite | HBV | IC | 50 | : 1.2 μg/mL (mix A+B+E) | ND |
| destruxin B [38] | destruxin B [83] | peptide | M. anisopliae | var. | dcjhyium; | O. formosanus | termite | HBV | IC | 50 | : 1.2 μg/mL (mix A+B+E) | ND |
| destruxin E [38] | destruxin E [83] | peptide | M. anisopliae | var. | dcjhyium | O. formosanus | termite | HBV | IC | 50 | : 1.2 μg/mL (mix A+B+E) | ND |
| amphiepicoccin A [11] | amphiepicoccin A [95] | alkaloid | Epicoccum nigrum | HDN17-88 | Amphilophus | sp. fish gill | HSV-2 | IC | 50 | : 70 μM | ND | |
| amphiepicoccin C [11] | amphiepicoccin C [95] | alkaloid | E. nigrum | HDN17-88 | Amphilophus | sp. fish gill | HSV-2 | IC | 50 | : 64 μM | ND | |
| amphiepicoccin F [11] | amphiepicoccin F [95] | alkaloid | E. nigrum | HDN17-88 | Amphilophus | sp. fish gill | HSV-2 | IC | 50: | 29 μM | ND | |
| aspergillipeptide D [39] | aspergillipeptide D [96] | peptide | Aspergillus | sp. SCSIO 41501 | gorgonian coral | HSV-1 | IC | 50 | : 7.93 μM | entry | ||
| aspergilol H [40] | aspergilol H [98] | polyketide | Aspergillus versicolor | SCSIO 41501 | deep sea sediment | HSV-1 | EC | 50 | = 4.68 μM | ND | ||
| aspergilol I [40] | aspergilol I [98] | polyketide | A. versicolor | SCSIO 41503 | deep sea sediment | HSV-1 | IC | 50 | = 6.25 μM | ND | ||
| coccoquinone A [40] | coccoquinone A [98] | polyketide | A. versicolor | SCSIO 41504 | deep sea sediment | HSV-1 | IC | 50 | = 3.12 μM | ND | ||
| trichobotrysin A [41] | trichobotrysin A [99] | alkaloid | Trichobotrys effuse | DFFSCS021 | deep sea sediment | HSV-1 | IC | 50 | = 3.08 μM | ND | ||
| trichobotrysin B [41] | trichobotrysin B [99] | alkaloid | Trichobotrys effuse | DFFSCS021 | deep sea sediment | HSV-1 | IC | 50 | = 9.37 μM | ND | ||
| trichobotrysin D [41] | trichobotrysin D [99] | alkaloid | Trichobotrys effuse | DFFSCS021 | deep sea sediment | HSV-1 | IC | 50 | = 3.12 μM | ND | ||
| 11a-dehydroxyisoterreulactone A [42] | 11a-dehydroxyisoterreulactone A [100] | terpenoid | Aspergillus terreus | SCSGAF0162 | gorgonian corals | Echinogorgia aurantiaca | HSV-1 | IC | 50 | = 16.4 μg/mL | ND | |
| arisugacin A [42] | arisugacin A [100] | terpenoid | Aspergillus terreus | SCSGAF0162 | gorgonian corals | E. aurantiaca | HSV-1 | IC | 50 | = 6.34 μg/mL | ND | |
| isobutyrolactone II [42] | isobutyrolactone II [100] | terpenoid | Aspergillus terreus | SCSGAF0162 | gorgonian corals | E. aurantiaca | HSV-1 | IC | 50 | = 21.8 μg/mL | ND | |
| aspernolide A [42] | aspernolide A [100] | terpenoid | Aspergillus terreus | SCSGAF0162 | gorgonian corals | E. aurantiaca | HSV-1 | IC | 50 | = 28.9 μg/mL | ND | |
| halovir A [43] | halovir A [101] | peptide | Scytalidium | sp. | NI | HSV-1 and HSV-2 | ED | 50 | = 1.1 μM (HSV-1) and 0.28 (HSV-2) | ND | ||
| halovir B [43] | halovir B [101] | peptide | Scytalidium | sp. | NI | HSV-1 | ED | 50 | = 3.5 μM | ND | ||
| halovir C [43] | halovir C [101] | peptide | Scytalidium | sp. | NI | HSV-1 | ED | 50 | = 2.2 μM | ND | ||
| halovir D [43] | halovir D [101] | peptide | Scytalidium | sp. | NI | HSV-1 | ED | 50 | = 2.0 μM | ND | ||
| halovir E [43] | halovir E [101] | peptide | Scytalidium | sp. | NI | HSV-1 | ED | 50 | = 3.1 μM | ND | ||
| balticolid [44] | balticolid [102] | polyketide | Ascomycetous fungus | driftwood | HSV-1 | IC | 50 | = 0.45 μM | ND | |||
| alternariol [45] | alternariol [106] | phenolic | Pleospora tarda | Ephedra aphylla | endphyte | HSV-1 | IC | 50 | = 13.5 μM | ND | ||
| alternariol-(9)-methyl ether [45] | alternariol-(9)-methyl ether [106] | phenolic | Pleospora tarda | E. aphylla | endophyte | HSV-1 | IC | 50 | = 21.3 μM | ND | ||
| oblongolide Z [46] | oblongolide Z [107] | polyketide | Phomopsis | sp. BCC 9789 | Musa acuminata | endophyte | HSV-1 | IC | 50 | : 14 μM | ND | |
| DHI [47] | DHI [113] | phenolic | Torrubiella tenuis | BCC 12732 | Homoptera scale insect | HSV-1 | IC | 50 | : 50 μg/mL | ND | ||
| cordyol C [48] | cordyol C [114] | polyketide | Cordyceps | sp. BCC 1861 | Homoptera-cicada nymph | HSV-1 | IC | 50 | : 1.3 μg/mL | ND | ||
| DTD [49] | DTD [117] | polyketide | Streptomyces hygroscopicus | 17997 | GdmP mutant | HSV-1 | IC | 50 | : 0.252 μgmol/L | ND | ||
| labyrinthopeptin A1/LabyA1 [50] | labyrinthopeptin A1/LabyA1 [118] | peptide | Actinomadura namibiensis | DSM 6313 | desert soil | HSV-1 and HSV-2 | EC | 50 | = 0.56 μM (HSV-1) and 0.32 μM (HSV-2) | entry | ||
| HIV-1 and HIV-2 | EC | 50 | = 2.0 μM (HIV-1) and 1.9 μM (HIV-2) | entry | ||||||||
| monogalactopyranose [51] | monogalactopyranose [120] | polyphenol | Acremonium | sp. BCC 14080 | palm leaf | HSV | IC | 50 | : 7.2 μM | ND | ||
| mellisol [52] | mellisol [121] | polyketide | Xylaria mellisii | BCC 1005 | NI | HSV | IC | 50 | : 10.5 μg/mL | ND | ||
| DOG [52] | DOG [121] | polyketide | Xylaria mellisii | BCC 1005 | NI | HSV | IC | 50 | : 8.4 μg/mL | ND | ||
| spirostaphylotrichin X [53] | spirostaphylotrichin X [126] | polyketide | Cochliobolus lunatus | SCSIO41401 | marine algae | H1N1 and H3N2 | IC | 50 | : 1.6 μM (H1N1) and 4.1 μM (H3N2) | replication | ||
| cladosin C [54] | cladosin C [127] | polyketide | Cladosporium sphaerospermum | 2005-01-E3 | deep sea sludge | H1N1 | IC | 50 | : 276 μM | ND | ||
| abyssomicin Y [50] | abyssomicin Y [118] | polyketide | Verrucosispora | sp. MS100137 | deep sea sediment | H1N1 | inhibition rate: 97.9% | ND | ||||
| purpurquinone B [55] | purpurquinone B [129] | polyketide | Penicillium purpurogenum | JS03-21 | acidic red soil | H1N1 | IC | 50 | : 61.3 μM | ND | ||
| purpurquinone C [55] | purpurquinone C [129] | polyketide | Penicillium purpurogenum | JS03-22 | acidic red soil | H1N1 | IC | 50 | : 64 μM | ND | ||
| purpurester A [55] | purpurester A [129] | polyketide | Penicillium purpurogenum | JS03-23 | acidic red soil | H1N1 | IC | 50 | : 85.3 μM | ND | ||
| TAN-931 [55] | TAN-931 [129] | polyketide | Penicillium purpurogenum | JS03-24 | acidic red soil | H1N1 | IC | 50 | : 58.6 μM | ND | ||
| pestalotiopsone B [56] | pestalotiopsone B [130] | polyketide | Diaporthe | sp. SCSIO 41011 | Rhizophora stylosa | mangrove endophte | H1N1 and H3N2 | IC | 50 | : 2.56 μM (H1N1) and 6.76 μM (H3N2) | ND | |
| pestalotiopsone F [56] | pestalotiopsone F [130] | polyketide | Diaporthe | sp. SCSIO 41012 | R. stylosa | mangrove endophte | H1N1 and H3N2 | IC | 50 | : 21.8 μM (H1N1) and 6.17 μM (H3N2) | ND | |
| DMXC [56] | DMXC [130] | polyketide | Diaporthe | sp. SCSIO 41013 | R. stylosa | mangrove endophte | H1N1 and H3N2 | IC | 50 | : 9.4 μM (H1N1) and 5.12 μM (H3N2) | ND | |
| 5-chloroisorotiorin [56] | 5-chloroisorotiorin [130] | polyketide | Diaporthe | sp. SCSIO 41014 | R. stylosa | mangrove endophte | H1N1 and H3N2 | IC | 50 | : 2.53 μM (H1N1) and 10.1 μM (H3N2) | ND | |
| 3-deoxo-4b-deoxypaxilline [57] | 3-deoxo-4b-deoxypaxilline [131] | alkaloid | Penicillium camemberti | mangrove sediment | H1N1 | IC | 50 | : 28.3 μM | ND | |||
| DCA [57] | DCA [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 38.9 μM | ND | ||
| DPT [57] | DPT [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 32.2 μM | ND | ||
| 9,10-diisopentenylpaxilline | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 73.3 μM | ND | |||
| TTD [57] | TTD [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 34.1 μM | ND | ||
| emindole SB [57] | emindole SB [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 26.2 μM | ND | ||
| 21-isopentenylpaxilline [57] | 21-isopentenylpaxilline [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 6.6 μM | ND | ||
| paspaline [57] | paspaline [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 77.9 μM | ND | ||
| paxilline [57] | paxilline [131] | alkaloid | P. camemberti | OUCMDZ-1492 | mangrove sediment | H1N1 | IC | 50 | : 17.7 μM | ND | ||
| (14S)-oxoglyantrypine [58] | (14S)-oxoglyantrypine [132] | alkaloid | Cladosporium | sp. PJX-41 | mangrove sediment | H1N1 | IC | 50 | : 85 μM | ND | ||
| norquinadoline A [58] | norquinadoline A [132] | alkaloid | Cladosporium | sp. PJX-42 | mangrove sediment | H1N1 | IC | 50 | : 82 μM | ND | ||
| deoxynortryptoquivaline [58] | deoxynortryptoquivaline [132] | alkaloid | Cladosporium | sp. PJX-43 | mangrove sediment | H1N1 | IC | 50 | : 85 μM | ND | ||
| deoxytryptoquivaline [58] | deoxytryptoquivaline [132] | alkaloid | Cladosporium | sp. PJX-44 | mangrove sediment | H1N1 | IC | 50 | : 85 μM | ND | ||
| tryptoquivaline [58] | tryptoquivaline [132] | alkaloid | Cladosporium | sp. PJX-45 | mangrove sediment | H1N1 | IC | 50 | : 89 μM | ND | ||
| quinadoline B [58] | quinadoline B [132] | alkaloid | Cladosporium | sp. PJX-46 | mangrove sediment | H1N1 | IC | 50 | : 82 μM | ND | ||
| 22-O-(N-Me-l-valyl)-21-epi-aflaquinolone B [59] | 22-O-(N-Me-l-valyl)-21-epi-aflaquinolone B [138] | alkaloid | Aspergillus | sp strain XS-2009 | Muricella abnormaliz | gorgonian | RSV | IC | 50 | : 0.042 μM | ND | |
| aflaquinolone D [59] | aflaquinolone D [138] | alkaloid | Aspergillus | sp strain XS-2009 | M. abnormaliz | gorgonian | RSV | IC | 50 | : 6.6 μM | ND | |
| aurasperone A [60] | aurasperone A [152] | polyphenol | Aspergillus niger | No.LC582533 | Phallusia nigra | tunicate | SARS-CoV-2 | IC | 50 | : 12.25 μM | replication | |
| neoechinulin A [30] | neoechinulin A [153] | alkaloid | Aspergillus fumigatus | MR2012 | marine sediment | SARS-CoV-2 | IC | 50 | : 0.47 μM | replication | ||
| aspulvinone D [61] | aspulvinone D [154] | polyphenol | Cladosporium | sp. 7951 | Paris polyphylla | endophyte | SARS-CoV-2 | IC | 50 | : 10.3 μM | replication | |
| aspulvinone M [61] | aspulvinone M [154] | polyphenol | Cladosporium | sp. 7951 | P. polyphylla | endophyte | SARS-CoV-2 | IC | 50 | : 9.4 μM | replication | |
| aspulvinone R [61] | aspulvinone R [154] | polyphenol | Cladosporium | sp. 7952 | P. polyphylla | endophyte | SARS-CoV-2 | IC | 50 | : 7.7 μM | replication |
Abbreviations: * ND: not yet described, * NI; no information, * DTM: 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran, * THA: 1,2,4,5-tetrahydroxy-7-((2R)-2-hydroxypropyl) anthracene-9,10-dione, * MDMX: methyl 6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylate, * DHI: 6,8-dihydroxy-3-hydroxymethyl isocoumarin, * DOG: 1,8-dihydroxynaphthol 1-O-glucopyranoside, * DMXC: 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate, * TTD: (6S,7R,10E,14E)-16-(1H-indol-3-yl)-2,6,10,14-tetramethylhexadeca-2,10,14-triene-6,7-diol, * DTD: 4,5-dihydro-thiazinogeldanamycin, * DCA: 4a-demethylpaspaline-4a-carboxylic acid, * DPT: 4a-demethylpaspaline-3,4,4a-triol.
Natural products made by fungi that thrive in unique marine environments have also been particularly useful in drug discovery. Marine fungi have been the source of the discovery of many novel bioactive natural compounds with anticancer, antifungal, cytotoxic, and antibacterial properties for the past decade [62][63][64][59,60,61]. Penicillium raistrickii IMB17-034, a marine-derived fungus, was cultured to isolate raistrickindole A and raistrickin. Both chemicals inhibited Huh7.5 human liver cells infected with HCV, with EC50 values of 5.7 and 7.0 μM, respectively [32][62]. Harzianoic acid A and B are sesquiterpene-based analogues discovered in the symbiotic relationship of the Trichoderma harzianum ascomycete fungus with sponges [65][63]. These purified compounds demonstrated high efficacy in lowering HCV RNA levels in Huh7.5 cells [65][63]. Furthermore, both compounds are proposed to block HCV entry into the host, with potential targets including the viral E1/E2 and host cell CD81 proteins [65][63]. In 2016, Nishikori and his colleagues discovered peniciherquamide C, produced by Penicillium herquei P14190 and isolated from seaweed collected in Toba, Mie, Japan, after being incubated at 37 °C for 1–2 weeks [33][64]. Its anti-HCV molecule has an IC50 of 5.1 μM [33][64]. Furthermore, the cyclo (L-Tyr-L-Pro) diketopiperazine isolated from the endophytic fungus Aspergillus versicolor isolated from the Red Sea black sponge Spongia officinalis significantly inhibited HCV replication by inhibiting the activity of the HCV NS3/4A protease with an IC50 value of 8.2 μg/mL [34][65]. Similarly, an ethyl acetate extract of the fungus Penicillium chrysogenum obtained from the red alga Liagora viscida also secretes antiviral metabolites that inhibit the HCV NS3/4A protease [66].
Endophytic fungi have also been identified as a significant source of secondary metabolites, due to their complex and dynamic interactions with host plants [67]. A growing body of evidence suggests that endophytic fungi metabolites play an essential role in plant immunity against herbivores and pathogen defense and establish symbiosis with the host plant [67][68][69][70][67,68,69,70]. These secondary metabolites are expected to be a novel source of natural antiviral compounds, due to their diverse biological activities and wide structural variety. The activities of 44 endophytic fungi isolated from the Red Sea sponge Hyrtios erectus were studied and screened [71]. HCV inhibition was observed in extracts of Penicillium chrysogenum MERVA42, Diaporthe rudis MERVA25, Auxarthron alboluteum MERVA32, Fusarium oxysporum MERVA39, Trichoderma harzianum MERVA44, Aspergillus versicolor MERVA29, Lophiostoma sp. MERVA36, and Penicillium polonicum MERVA43 [71]. In addition, the HCV protease inhibitory activity of fourty-eight endophytic fungal strains isolated and purified from ten Egyptian medicinal plants was investigated. Alternaria alternata PGL-3, Cochlibolus lunatus PML-17, Nigrospora sphaerica EPS-38, and Emerecilla nidulans RPL-21 extracts inhibited the most HCV NS3/4A protease [72].
2. Anti-Hepatitis B Virus
People who are infected with HBV, of which there are over 350 million worldwide, are responsible for up to 80% of cases of primary liver cancer [73]. This disease is the leading cause of death worldwide. HBV infection may be responsible for 3% of total mortality in countries where HBV carrier rates reach 10%, a higher level than the mortality rate associated with polio before the introduction of the polio vaccine [74]. The WHO recommends the use of oral treatments, including tenofovir or entecavir, as the most potent drugs to suppress HBV [75]. A number of natural products produced by microorganisms, as shown in Table 1, have the potential to be developed into anti-HBV medications.
As part of the effort to discover new bioactive metabolites with anti-HBV properties from microbes, Ai and colleagues isolated 7-dehydroxyl-zinniol from Alternaria solani, an endophytic fungal strain found in the roots of the perennial herb Aconitum transsectum, which was shown to have moderate antiviral efficacy against HBV in the HBV-transfected HepG2.2.15 cell line (IC50 value of 0.38 μM), as evidenced by a decrease in hepatitis B surface antigen (HBsAg) secretion [35][76]. Furthermore, Jin and his colleagues investigated the secondary metabolite of the acidophilic fungus Penicillium sp. (strain OUCMDZ-4736) isolated from the root sediment of the mangrove Acanthus ilicifolius, also known as the holy mangrove [36][77]. Three new anthraquinone derivatives were successfully isolated from the low-pH fermentation broth of the OUCMDZ-4736 strain [36][77]. However, only two of them demonstrated anti-HBV activity, including 1-hydroxyisorhodoptilometrin and methyl 6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylate, which significantly inhibited HepG2.2.15 human hepatoblastoma cells with IC50 of 4.63 and 11.35 μM, respectively [36][77]. Both could prevent HepG2.2.15 cells from secreting HBsAg and (hepatitis B early antigen) HBeAg [36][77]. Regarding anti-HBV activity, both outperformed the positive control, lamivudine (IC50: 68.94 μM) [36][77]. Other derivatives produced by the OUCMDZ-4736 strain, on the other hand, did not show anti-HBV activity [36][77]. Another fungus, Talaromyces sp., produces secondary metabolites with anti-hepatitis properties, such as vanitaracin A. It is a tricyclic polyketide isolated from Talaromyces sp. broth. Vanitaracin A has potent anti-HBV activity in HBV-susceptible HepG2-hNTCP-C4 cells, with an IC50 value of 10.5 μM [37][78]. Furthermore, this molecule inhibits HBV viral entry signaling pathways in human hepatocytes. All HBV genotypes (A-D) were recognized by vanitaracin A, including a drug-resistant HBV isolate. According to these findings, vanitaracin A could be used in antiviral treatments to prevent HBV recurrence [76][79].
Even though pathogenic microbes, such as fungi, can cause severe diseases in hosts, many of them produce bioactive chemicals that could be used to develop new drugs [77][78][79][80,81,82]. Dong and colleagues investigated the anti-HBV properties of crude destruxins (a combination of cyclodepsipeptidic molecules, including destruxin A, B, and E, isolated from Metarhizium anisopliae var. dcjhyium, an entomopathogenic fungus that has a symbiotic relationship with the termite Odontoternes formosanus [38][83]. In HepG2.2.15 cells, these crude destruxins inhibited HBV-DNA replication, as well as HBsAg and HBeAg production [38][83]. An in vivo trial using ducks infected with duck HBV and treated for 15 days with crude destruxins revealed that the treated group had significantly lower levels of duck serum DHBV-DNA than the control group [38][83]. Furthermore, a pure form of destruxin B from the plant pathogenic fungus Alternaria brassicae suppresses HBsAg gene expression in human hepatoma Hep3B cells. Destruxin B had no negative effects on cell viability, implying that it could be developed in the future as a specialized anti-HBV medication [80][84].