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Frediansyah, A.;  Sofyantoro, F.;  Alhumaid, S.;  Mutair, A.A.;  Albayat, H.;  Altaweil, H.I.;  Al-Afghani, H.M.;  Alramadhan, A.A.;  Alghazal, M.R.;  Turkistani, S.A.; et al. Microbial Natural Products with Anti-Hepatitis Virus. Encyclopedia. Available online: https://encyclopedia.pub/entry/25120 (accessed on 06 December 2025).
Frediansyah A,  Sofyantoro F,  Alhumaid S,  Mutair AA,  Albayat H,  Altaweil HI, et al. Microbial Natural Products with Anti-Hepatitis Virus. Encyclopedia. Available at: https://encyclopedia.pub/entry/25120. Accessed December 06, 2025.
Frediansyah, Andri, Fajar Sofyantoro, Saad Alhumaid, Abbas Al Mutair, Hawra Albayat, Hayyan I. Altaweil, Hani M. Al-Afghani, Abdullah A. Alramadhan, Mariam R. Alghazal, Safaa A. Turkistani, et al. "Microbial Natural Products with Anti-Hepatitis Virus" Encyclopedia, https://encyclopedia.pub/entry/25120 (accessed December 06, 2025).
Frediansyah, A.,  Sofyantoro, F.,  Alhumaid, S.,  Mutair, A.A.,  Albayat, H.,  Altaweil, H.I.,  Al-Afghani, H.M.,  Alramadhan, A.A.,  Alghazal, M.R.,  Turkistani, S.A.,  Abuzaid, A.A., & Rabaan, A.A. (2022, July 14). Microbial Natural Products with Anti-Hepatitis Virus. In Encyclopedia. https://encyclopedia.pub/entry/25120
Frediansyah, Andri, et al. "Microbial Natural Products with Anti-Hepatitis Virus." Encyclopedia. Web. 14 July, 2022.
Microbial Natural Products with Anti-Hepatitis Virus
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27134305

The hepatitis virus is one of the major burdens on the global health system. There are 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) 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]. 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], NS5B [3], and NS3/4A [4]. 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]. 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]. Nakajima and his colleagues later demonstrated that NeoB inhibited the development of infectious HCV in Huh-7 cells [7]. 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]. To achieve high yields, Nishiuchi and his colleagues also developed the synthetic antiviral agent NeoB and other derivatives [8].
Table 1. Natural product produce by microbes and its target.
Compound Name [Ref.] Compound Type Microbial Strain Strain Origin/Host Viral Target IC50/EC50/ED50 Target Inhibition
alachalasin A [9] alkaloid Podospora vesticola XJ03-56-1 glacier HIV-1 EC50 = 8.01 μM ND
pestalofone A [10] terpenoid Pestalotiopsis fici W106-1 plant endophyte HIV-1 EC50 = 90.4 μM ND
pestalofone B [10] terpenoid P. fici W106-1 plant endophyte HIV-1 EC50 = 64.0 μM ND
pestalofone E [10] terpenoid P. fici W106-2 plant endophyte HIV-1 EC50 = 93.7 μM ND
pestaloficiol G [10] terpenoid P. fici W106-3 plant endophyte HIV-1 EC50 = 89.2 μM ND
pestaloficiol H [10] terpenoid P. fici W106-4 plant endophyte HIV-1 EC50 = 89.2 μM ND
pestaloficiol J [10] terpenoid P. fici W106-5 plant endophyte HIV-1 EC50 = 8 μM ND
pestaloficiol K [10] terpenoid P. fici W106-6 plant endophyte HIV-1 EC50 = 78.2 μM ND
epicoccin G [11] alkaloid Epicoccum nigrum XZC04-CS-302 Cordyceps sinensis fungus HIV-1 EC50 = 13.5 μM ND
epicoccin H [11] alkaloid E. nigrum XZC04-CS-302 C. sinensis HIV-1 EC50 = 42.2 μM ND
diphenylalazine A [11] peptide E. nigrum XZC04-CS-302 C. sinensis HIV-1 EC50 = 27.9 μM ND
bacillamide B [12] peptide Tricladium sp. No. 2520 soil in which C. sinensis grow HIV-1 EC50 = 24.8 μM ND
armochaetoglobin K [13] alkaloid Chaetomium globosum TW 1-1 Armadillidium vulgare insect HIV-1 EC50 = 1.23 μM ND
armochaetoglobin L [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.48 μM ND
armochaetoglobin M [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.55μM ND
armochaetoglobin N [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.25 μM ND
armochaetoglobin O [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.61 μM ND
armochaetoglobin P [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.68 μM ND
armochaetoglobin Q [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.31 μM ND
armochaetoglobin R [13] alkaloid C. globosum TW 1-1 A. vulgare insect HIV-1 EC50 = 0.34 μM ND
stachybotrin D [14] terpenoid Stachybotrys chartarum MXH-X73 Xestospongia testudinaris sponge HIV-1 EC50 = 8.4 μM replication
stachybotrysam A [15] alkaloid S. chartarum CGMCC 3.5365. ND HIV-1 EC50 = 9.3 μM ND
stachybotrysam B [15] alkaloid S. chartarum CGMCC 3.5365. ND HIV-1 EC50 = 1.0 μM ND
stachybotrysam C [15] alkaloid S. chartarum CGMCC 3.5365. ND HIV-1 EC50 = 9.6 μM ND
chartarutine B [16] alkaloid S. chartarum WGC-25C-6 Niphates sp. sponge HIV-1 IC50 = 4.90 μM ND
chartarutine G [16] alkaloid S. chartarum WGC-25C-6 Niphates sp. sponge HIV-1 IC50 = 5.57 μM ND
chartarutine H [16] alkaloid S. chartarum WGC-25C-6 Niphates sp. sponge HIV-1 IC50 = 5.58 μM ND
malformin C [17] peptide Aspergillus niger SCSIO Jcsw6F30 marine HIV-1 IC50 = 1.4 μM entry
aspernigrin C [18] alkaloid A. niger SCSIO Jcsw6F30 marine HIV-1 IC50 = 4.7 μM entry
eutypellazine E [19] alkaloid Eutypella sp. MCCC 3A00281 deep sea sediment HIV-1 IC50 = 3.2 μM ND
truncateol O [20] terpenoid Truncatella angustata XSB-01-43 Amphimedon sp. sponge HIV-1 and H1N1 IC50 = 39.0 μM (HIV) and 30.4 μM (H1N1) ND
truncateol P [20] terpenoid T. angustata XSB-01-43 Amphimedon sp. sponge HIV-1 IC50 = 16.1 μM ND
penicillixanthone A [21] polyketide Aspergillus fumigatus jellyfish HIV-1 IC50 = 0.26 μM entry
DTM [22] polyketide C. globosum deep sea sediment HIV-1 75.1% at 20 μg/mL ND
epicoccone B [22] polyketide C. globosum deep sea sediment HIV-1 88.4% at 20 μg/mL ND
xylariol [22] polyketide C. globosum deep sea sediment HIV-1 70.2% at 20 μg/mL ND
phomonaphthalenone A [23] polyketide Phomopsis sp. HCCB04730 Stephania japonica-plant endophyte HIV-1 IC50: 11.6 μg/mL ND
bostrycoidin [23] polyketide Phomopsis sp. HCCB04730 S. japonica plant endophyte HIV-1 IC50: 9.4 μg/mL ND
altertoxin I [24] phenalene Alternaria tenuissima QUE1Se Quercus emoryi plant endophyte HIV-1 IC50: 1.42 μM ND
altertoxin II [24] phenalene A. tenuissima QUE1Se Q. emoryi plant endophyte HIV-1 IC50: 0.21 μM ND
altertoxin III [24] phenalene A. tenuissima QUE1Se Q. emoryi plant endophyte HIV-1 IC50: 0.29 μM ND
alternariol 5-O-methyl ether [25] phenolic Colletotrichum sp plant endophyte HIV-1 EC50: 30.9 μM replication
ergokonin A [26] terpenoid Trichoderma sp. Xy24 Xylocarpus granatum plant endophyte HIV-1 IC50: 22.3 μM ND
ergokonin B [26] terpenoid Trichoderma sp. Xy24 X. granatum plant endophyte HIV-1 IC50: 1.9 μM ND
sorrentanone [26] terpenoid Trichoderma sp. Xy24 X. granatum plant endophyte HIV-1 IC50: 4.7 μM ND
cerevisterol [26] terpenoid Trichoderma sp. Xy24 X. granatum plant endophyte HIV-1 IC50: 9.3 μM ND
phomopsone B [27] alkaloid Phomopsis sp. CGMCC 5416 Achyranthes bidentata plant endophyte HIV-1 IC50: 7.6 μmol/L ND
phomopsone C [27] alkaloid Phomopsis sp. CGMCC 5416 A. bidentata plant endophyte HIV-1 IC50: 0.5 μmol/L ND
pericochlorosin B [28] polyketide Periconia sp. F-31 plant endophyte HIV-1 IC50: 2.2 μM ND
asperphenalenone A [29] alkaloid Aspergillus sp. Kadsura longipedunculata plant endophyte HIV-1 IC50: 4.5 μM ND
asperphenalenone D [29] alkaloid Aspergillus sp. K. longipedunculata plant endophyte HIV-1 IC50: 2.4 μM ND
cytochalasin Z8 [29] alkaloid Aspergillus sp. K. longipedunculata plant endophyte HIV-1 IC50: 9.2 μM ND
epicocconigrone A [29] alkaloid Aspergillus sp. K. longipedunculata plant endophyte HIV-1 IC50: 6.6 μM ND
neoechinulin B/NeoB [6][30][31] alkaloid Aspergillus amstelodami ND HCV and SARS-CoV-2 IC50: 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] alkaloid Penicillium raistrickii IMB17-034 mangrove sediment HCV EC50: 5.7 μM ND
raistrickin [32] alkaloid P. raistrickii IMB17-035 mangrove sediment HCV EC50: 7.0 μM ND
sclerotigenin [32] alkaloid P. raistrickii IMB17-036 mangrove sediment HCV EC50: 5.8 μM ND
harzianoic acid A [26] terpenoid Trichoderma harzianum LZDX-32-08 Xestospongia testudinaria sponge HCV IC50: 5.5 μM entry
harzianoic acid B [26] terpenoid T. harzianum LZDX-32-08 X. testudinaria sponge HCV IC50: 42.9 μM entry
peniciherquamide C [33] peptide Penicillium herquei P14190 seaweed HCV IC50: 5.1 μM ND
cyclo (L-Tyr-L-Pro) [34] peptide Aspergillus versicolor Spongia officinalis sponge HCV IC50: 8.2 μg/mL replication
7-dehydroxyl-zinniol [35] alkaloid Alternia solani Aconitum transsectum plant endophyte HBV IC50: 0.38 mM ND
THA [36] polyketide Penicillium sp. OUCMDZ-4736 mangrove sediment HBV IC50: 4.63 μM ND
MDMX [36] polyketide Penicillium sp. OUCMDZ-4736 mangrove sediment HBV IC50: 11.35 μM ND
vanitaracin A [37] polyketide Talaromyces sp. sand HBV IC50: 10.58 μM entry
destruxin A [38] peptide Metarhizium anisopliae var. dcjhyium Odontoternes formosanus termite HBV IC50: 1.2 μg/mL (mix A+B+E) ND
destruxin B [38] peptide M. anisopliae var. dcjhyium; O. formosanus termite HBV IC50: 1.2 μg/mL (mix A+B+E) ND
destruxin E [38] peptide M. anisopliae var. dcjhyium O. formosanus termite HBV IC50: 1.2 μg/mL (mix A+B+E) ND
amphiepicoccin A [11] alkaloid Epicoccum nigrum HDN17-88 Amphilophus sp. fish gill HSV-2 IC50: 70 μM ND
amphiepicoccin C [11] alkaloid E. nigrum HDN17-88 Amphilophus sp. fish gill HSV-2 IC50: 64 μM ND
amphiepicoccin F [11] alkaloid E. nigrum HDN17-88 Amphilophus sp. fish gill HSV-2 IC50: 29 μM ND
aspergillipeptide D [39] peptide Aspergillus sp. SCSIO 41501 gorgonian coral HSV-1 IC50: 7.93 μM entry
aspergilol H [40] polyketide Aspergillus versicolor SCSIO 41501 deep sea sediment HSV-1 EC50 = 4.68 μM ND
aspergilol I [40] polyketide A. versicolor SCSIO 41503 deep sea sediment HSV-1 IC50 = 6.25 μM ND
coccoquinone A [40] polyketide A. versicolor SCSIO 41504 deep sea sediment HSV-1 IC50 = 3.12 μM ND
trichobotrysin A [41] alkaloid Trichobotrys effuse DFFSCS021 deep sea sediment HSV-1 IC50 = 3.08 μM ND
trichobotrysin B [41] alkaloid Trichobotrys effuse DFFSCS021 deep sea sediment HSV-1 IC50 = 9.37 μM ND
trichobotrysin D [41] alkaloid Trichobotrys effuse DFFSCS021 deep sea sediment HSV-1 IC50 = 3.12 μM ND
11a-dehydroxyisoterreulactone A [42] terpenoid Aspergillus terreus SCSGAF0162 gorgonian corals Echinogorgia aurantiaca HSV-1 IC50 = 16.4 μg/mL ND
arisugacin A [42] terpenoid Aspergillus terreus SCSGAF0162 gorgonian corals E. aurantiaca HSV-1 IC50 = 6.34 μg/mL ND
isobutyrolactone II [42] terpenoid Aspergillus terreus SCSGAF0162 gorgonian corals E. aurantiaca HSV-1 IC50 = 21.8 μg/mL ND
aspernolide A [42] terpenoid Aspergillus terreus SCSGAF0162 gorgonian corals E. aurantiaca HSV-1 IC50 = 28.9 μg/mL ND
halovir A [43] peptide Scytalidium sp. NI HSV-1 and HSV-2 ED50 = 1.1 μM (HSV-1) and 0.28 (HSV-2) ND
halovir B [43] peptide Scytalidium sp. NI HSV-1 ED50 = 3.5 μM ND
halovir C [43] peptide Scytalidium sp. NI HSV-1 ED50 = 2.2 μM ND
halovir D [43] peptide Scytalidium sp. NI HSV-1 ED50 = 2.0 μM ND
halovir E [43] peptide Scytalidium sp. NI HSV-1 ED50 = 3.1 μM ND
balticolid [44] polyketide Ascomycetous fungus driftwood HSV-1 IC50 = 0.45 μM ND
alternariol [45] phenolic Pleospora tarda Ephedra aphylla endphyte HSV-1 IC50 = 13.5 μM ND
alternariol-(9)-methyl ether [45] phenolic Pleospora tarda E. aphylla endophyte HSV-1 IC50 = 21.3 μM ND
oblongolide Z [46] polyketide Phomopsis sp. BCC 9789 Musa acuminata endophyte HSV-1 IC50: 14 μM ND
DHI [47] phenolic Torrubiella tenuis BCC 12732 Homoptera scale insect HSV-1 IC50: 50 μg/mL ND
cordyol C [48] polyketide Cordyceps sp. BCC 1861 Homoptera-cicada nymph HSV-1 IC50: 1.3 μg/mL ND
DTD [49] polyketide Streptomyces hygroscopicus 17997 GdmP mutant HSV-1 IC50: 0.252 μgmol/L ND
labyrinthopeptin A1/LabyA1 [50] peptide Actinomadura namibiensis DSM 6313 desert soil HSV-1 and HSV-2 EC50 = 0.56 μM (HSV-1) and 0.32 μM (HSV-2) entry
HIV-1 and HIV-2 EC50 = 2.0 μM (HIV-1) and 1.9 μM (HIV-2) entry
monogalactopyranose [51] polyphenol Acremonium sp. BCC 14080 palm leaf HSV IC50: 7.2 μM ND
mellisol [52] polyketide Xylaria mellisii BCC 1005 NI HSV IC50: 10.5 μg/mL ND
DOG [52] polyketide Xylaria mellisii BCC 1005 NI HSV IC50: 8.4 μg/mL ND
spirostaphylotrichin X [53] polyketide Cochliobolus lunatus SCSIO41401 marine algae H1N1 and H3N2 IC50: 1.6 μM (H1N1) and 4.1 μM (H3N2) replication
cladosin C [54] polyketide Cladosporium sphaerospermum 2005-01-E3 deep sea sludge H1N1 IC50: 276 μM ND
abyssomicin Y [50] polyketide Verrucosispora sp. MS100137 deep sea sediment H1N1 inhibition rate: 97.9% ND
purpurquinone B [55] polyketide Penicillium purpurogenum JS03-21 acidic red soil H1N1 IC50: 61.3 μM ND
purpurquinone C [55] polyketide Penicillium purpurogenum JS03-22 acidic red soil H1N1 IC50: 64 μM ND
purpurester A [55] polyketide Penicillium purpurogenum JS03-23 acidic red soil H1N1 IC50: 85.3 μM ND
TAN-931 [55] polyketide Penicillium purpurogenum JS03-24 acidic red soil H1N1 IC50: 58.6 μM ND
pestalotiopsone B [56] polyketide Diaporthe sp. SCSIO 41011 Rhizophora stylosa mangrove endophte H1N1 and H3N2 IC50: 2.56 μM (H1N1) and 6.76 μM (H3N2) ND
pestalotiopsone F [56] polyketide Diaporthe sp. SCSIO 41012 R. stylosa mangrove endophte H1N1 and H3N2 IC50: 21.8 μM (H1N1) and 6.17 μM (H3N2) ND
DMXC [56] polyketide Diaporthe sp. SCSIO 41013 R. stylosa mangrove endophte H1N1 and H3N2 IC50: 9.4 μM (H1N1) and 5.12 μM (H3N2) ND
5-chloroisorotiorin [56] polyketide Diaporthe sp. SCSIO 41014 R. stylosa mangrove endophte H1N1 and H3N2 IC50: 2.53 μM (H1N1) and 10.1 μM (H3N2) ND
3-deoxo-4b-deoxypaxilline [57] alkaloid Penicillium camemberti mangrove sediment H1N1 IC50: 28.3 μM ND
DCA [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 38.9 μM ND
DPT [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 32.2 μM ND
9,10-diisopentenylpaxilline alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 73.3 μM ND
TTD [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 34.1 μM ND
emindole SB [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 26.2 μM ND
21-isopentenylpaxilline [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 6.6 μM ND
paspaline [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 77.9 μM ND
paxilline [57] alkaloid P. camemberti OUCMDZ-1492 mangrove sediment H1N1 IC50: 17.7 μM ND
(14S)-oxoglyantrypine [58] alkaloid Cladosporium sp. PJX-41 mangrove sediment H1N1 IC50: 85 μM ND
norquinadoline A [58] alkaloid Cladosporium sp. PJX-42 mangrove sediment H1N1 IC50: 82 μM ND
deoxynortryptoquivaline [58] alkaloid Cladosporium sp. PJX-43 mangrove sediment H1N1 IC50: 85 μM ND
deoxytryptoquivaline [58] alkaloid Cladosporium sp. PJX-44 mangrove sediment H1N1 IC50: 85 μM ND
tryptoquivaline [58] alkaloid Cladosporium sp. PJX-45 mangrove sediment H1N1 IC50: 89 μM ND
quinadoline B [58] alkaloid Cladosporium sp. PJX-46 mangrove sediment H1N1 IC50: 82 μM ND
22-O-(N-Me-l-valyl)-21-epi-aflaquinolone B [59] alkaloid Aspergillus sp strain XS-2009 Muricella abnormaliz gorgonian RSV IC50: 0.042 μM ND
aflaquinolone D [59] alkaloid Aspergillus sp strain XS-2009 M. abnormaliz gorgonian RSV IC50: 6.6 μM ND
aurasperone A [60] polyphenol Aspergillus niger No.LC582533 Phallusia nigra tunicate SARS-CoV-2 IC50: 12.25 μM replication
neoechinulin A [30] alkaloid Aspergillus fumigatus MR2012 marine sediment SARS-CoV-2 IC50: 0.47 μM replication
aspulvinone D [61] polyphenol Cladosporium sp. 7951 Paris polyphylla endophyte SARS-CoV-2 IC50: 10.3 μM replication
aspulvinone M [61] polyphenol Cladosporium sp. 7951 P. polyphylla endophyte SARS-CoV-2 IC50: 9.4 μM replication
aspulvinone R [61] polyphenol Cladosporium sp. 7952 P. polyphylla endophyte SARS-CoV-2 IC50: 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]. 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]. Harzianoic acid A and B are sesquiterpene-based analogues discovered in the symbiotic relationship of the Trichoderma harzianum ascomycete fungus with sponges [65]. These purified compounds demonstrated high efficacy in lowering HCV RNA levels in Huh7.5 cells [65]. 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]. 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]. Its anti-HCV molecule has an IC50 of 5.1 μM [33]. 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]. 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]. 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]. 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]. Three new anthraquinone derivatives were successfully isolated from the low-pH fermentation broth of the OUCMDZ-4736 strain [36]. 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]. Both could prevent HepG2.2.15 cells from secreting HBsAg and (hepatitis B early antigen) HBeAg [36]. Regarding anti-HBV activity, both outperformed the positive control, lamivudine (IC50: 68.94 μM) [36]. Other derivatives produced by the OUCMDZ-4736 strain, on the other hand, did not show anti-HBV activity [36]. 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]. 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].
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]. 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]. In HepG2.2.15 cells, these crude destruxins inhibited HBV-DNA replication, as well as HBsAg and HBeAg production [38]. 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]. 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].

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Andri Frediansyah , Fajar Sofyantoro , Saad Alhumaid , Abbas Al Mutair ,
Hawra Albayat
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Hayyan I. Altaweil
, Hani M. Al-Afghani ,
Abdullah A. AlRamadhan
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Mariam R. AlGhazal
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Safaa A. Turkistani
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Abdulmonem A. Abuzaid
, Ali A. Rabaan
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