Fungal Secondary Metabolite Exophillic Acid Selectively Inhibits the Entry of Hepatitis B and D Viruses

Abstract

Current anti-hepatitis B virus (HBV) drugs are suppressive but not curative for HBV infection, so there is considerable demand for the development of new anti-HBV agents. In this study, we found that fungus-derived exophillic acid inhibits HBV infection with a 50% maximal inhibitory concentration (IC50) of 1.1 µM and a 50% cytotoxic concentration (CC50) of >30 µM in primary human hepatocytes. Exophillic acid inhibited preS1-mediated viral attachment to cells but did not affect intracellular HBV replication. Exophillic acid appears to target the host cells to reduce their susceptibility to viral attachment rather than acting on the viral particles. We found that exophillic acid interacted with the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP). Exophillic acid impaired the uptake of bile acid, the original function of NTCP. Consistent with our hypothesis that it affects NTCP, exophillic acid inhibited infection with HBV and hepatitis D virus (HDV), but not that of hepatitis C virus. Moreover, exophillic acid showed a pan-genotypic anti-HBV effect. We thus identified the anti-HBV/HDV activity of exophillic acid and revealed its mode of action. Exophillic acid is expected to be a potential new lead compound for the development of antiviral agents.

Synthesis and Insecticidal Activity Evaluation of Potential Insecticidal Natural Product Borrelidin Analogs Toward New Pesticides

“…All reagents and solvents were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). 1 H and 13 C NMR spectra were measured using a JNM-ECA 500 (JEOL, Tokyo, Japan) at 500 and 125 MHz, respectively (Figures S1−S40). Chemical shifts are expressed in ppm downfield from the internal solvent peaks for CDCl 3 ( 1 H; δ = 7.26 ppm, 13 C; δ = 77.16 ppm) and CD 3 OD ( 1 H; δ = 3.31 ppm, 13 C; δ = 49.00 ppm) and J values were given in Hertz.…”

“…1.29 (t, 3H, J = 7.1 Hz), 1.25−1.17 (m, 1H), 1.15−1.07 (m, 1H), 1.04 (d, 3H, J = 6.3 Hz), 1.00−0.90 (m, 1H), 0.83 (d, 3H, J = 6.5 Hz), 0.80 (dd, 6H, J = 6.8, 2.3 Hz), 0.76−0.68 (m, 1H). 13 ( 4 -( ( ( ( 1 R , 2 R ) -2 -((2S,4E,6Z,8R,9S,11R,13S,15S,16S)-7-Cyano-8,16-dihydroxy-9,11,13,15-tetramethyl-18-oxooxacyclooctadeca-4,6-dien-2-yl)cyclopentane-1-carbonyl)thio)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxybenzoic acid (9c) was prepared by adding 4-azidosalicylic acid (9.9 mg, 55.2 μmol) according to the general method for preparation of triazole derivatives. The residue was purified by prep.…”

“…1 H NMR (500 MHz, CD 3 OD): δ (ppm) 8.52 (s, 1H), 8.13 (d, 2H, J = 8.5 Hz), 7.97 (d, 1H, J = 7.9 Hz), 7.85 (d, 2H, J = 9.2 Hz), 7.04 (d, 1H, J = 8.5 Hz), 6.90 (d, 1H, J = 11.0 Hz), 6.57 (dd, 1H, J = 14.6, 11.6 Hz), 6.29 (ddd, 1H, J = 14.7, 9.9, 4.9 Hz), 4.98−4.92 (m, 1H), 4.36 (d, 1H, J = 14.8 Hz), 4.23 (d, 1H, J = 14.8 Hz), 4.16 (d, 1H, J = 10.1 Hz), 3.84 (dt, 1H, J = 10.1, 2.6 Hz), 2.85−2.78 (m, 2H), 2.60− 2.46 (m, 2H), 2.20 (dd, 1H, J = 15.6, 3.2 Hz), 2.12−2.06 (m, 1H), 2.05−1.98 (m, 2H), 1.83−1.70 (m, 6H), 1.63−1.53 (m, 1H), 1.49− 1.39 (m, 1H), 1.16 (t, 1H, J = 12.6 Hz), 1.01 (d, 3H, J = 6.9 Hz), 0.97−0.88 (m, 2H), 0.81 (d, 3H, J = 6.3 Hz), 0.77 (d, 3H, J = 6.0 Hz), 0.67 (d, 3H, J = 6.9 Hz), 0.65−0.61 (m, 1H). 13 2S,4E,6Z,8R,9S,11R,13S,15S,16S)-7-cyano-8,16-dihydroxy-9,11,13,15-tetramethyl-18-oxooxacyclooctadeca-4,6-dien-2yl)cyclopentane-1-carbonyl)thio)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic acid (9e) was prepared by adding cis-4-azido-N-(tert-butoxycarbonyl)-L-proline (14.1 mg, 55.2 μmol) according to the general method for preparation of triazole derivatives. The residue was purified by prep.…”

“…13 C NMR (125 MHz, CD 3 OD): δ (ppm) 202.76, 173.13, 155.75, 145.32, 139.95, 128.96, 123.58, 119.91, 117.47, 81.79, 81.52, 77.12, 72.89, 72.74, 59.61, 58.60, 58.22, 52.03, 51.87, 49.85, 47.01, 44.47, 39.04, 38.39, 37.40, 37.03, 36.97, 36.46, 35.93, 33.58, 30.95, 28.71, 28.58, 27.65, 26.63, 24.22, 20.91, 18.81, 15.40. HR-ESI-MS [M + H] + m/z found for 800.4276 (calcd.…”

The Establishment of a Highly Sensitive Insecticidal Activity Detection System Using Silkworm First Instar Larvae Enables an Efficient Search Method for Insecticide Seed Compounds

“…The insecticidal activity of 26 pesticide standards was also evaluated using CCW first instar larvae, and the insecticide sensitivity of first instar larvae between silkworm and CCW was compared. In addition, 724 compounds in the O̅mura Natural Compound (O̅NC) library − were screened to rediscover the potent insecticidal compounds. As a result, natural compounds which showed insecticidal activity against silkworm first instar larvae at below 100 ppm were found.…”