(4R,6S)-2-Dihydromenisdaurilide is a Butenolide that Efficiently Inhibits Hepatitis C Virus Entry

Abstract

Without a vaccine, hepatitis C virus (HCV) remains a significant threat, putting 170–300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma. Although the direct-acting antivirals targeting HCV replication have revolutionized the treatment of hepatitis C, several obstacles persist, including resistance development, potential side-effects, and the prohibitive cost that limits their availability. Furthermore, treatment of HCV re-infection in liver transplantation remains a significant challenge. Developing novel antivirals that target viral entry could help expand the scope of HCV therapeutics and treatment strategies. Herein, we report (4R,6S)-2-dihydromenisdaurilide (DHMD), a natural butenolide, as an efficient inhibitor of HCV entry. Specifically, DHMD potently inhibited HCV infection at non-cytotoxic concentration. Examination on the viral life cycle demonstrated that DHMD selectively targeted the early steps of infection while leaving viral replication/translation and assembly/release unaffected. Furthermore, DHMD did not induce an antiviral interferon response. Mechanistic dissection of HCV entry revealed that DHMD could inactivate cell-free virus, abrogate viral attachment, and inhibit viral entry/fusion, with the most pronounced effect observed against the viral adsorption phase as validated using ELISA and confocal microscopy. Due to its potency, DHMD may be of value for further development as an entry inhibitor against HCV, particularly for application in transplant setting.

A plant‐derived dehydrorotenoid: a new inhibitor of hepatitis C virus entry

“…Till date there is no protective vaccine for the prevention of HCV infection, and therapeutic options to combat chronic hepatitis are still limited. However, treatment with DAAs is fraught with limitations associated with severe sideeffects and emergence of resistant viruses [9][10][11][12][13][14][15]. The recently approved direct-acting antivirals (DAAs) that inhibit HCV NS3/4A protease or NS5B polymerase activity when included in the treatment regimen have dramatically increased the SVR and improved treatment options [4][5][6][7][8].…”

“…The recently approved direct-acting antivirals (DAAs) that inhibit HCV NS3/4A protease or NS5B polymerase activity when included in the treatment regimen have dramatically increased the SVR and improved treatment options [4][5][6][7][8]. However, treatment with DAAs is fraught with limitations associated with severe sideeffects and emergence of resistant viruses [9][10][11][12][13][14][15]. The high expense of the current therapy restrain their use in developing countries where infection is most prevalent [16], thereby demonstrating the need to develop new, well tolerated and more efficient antivirals with low production cost.…”

Antifungal Triazole Posaconazole Targets an Early Stage of the Parechovirus A3 Life Cycle

“…The time course and time-of-drug-addition assays suggested that POS exerts its antiviral effect early in the PeV-A3 infection cycle, independent of interaction with the Vero-P cells. To further demonstrate it directly targets the virus, we performed in vitro synchronized infection assays (18) to evaluate the antiviral effect of POS when combined with PeV-A3 prior to inoculation of cells (free virus particles), on PeV-A3 attachment, and on PeV-A3 entry (Fig. 3A and B).…”

“…3A and B). At this temperature, the viral particles bind to the cell surface but entry is prevented (18). After washing to remove unbound virus and drug, the cells were shifted to 35°C to allow the infection to progress.…”

Strategies to Preclude Hepatitis C Virus Entry

“…SSb2 could inactivate cell-free HCV particles and was suggested to target the glycoprotein E2 in mediating its antiviral effect against HCV infection. Several other natural compounds including the gallic acid (GA) extracted from Limonium sinense [103], the hydrolyzable tannins chebulagic acid (CHLA) and punicalagin (PUG) [104], and the hepatoprotective plant Phyllanthus urinariaderived monolactone loliolide (LOD) [105] and butenolide (4R,6S)-2-dihydromenisdaurilide (DHMD) [106] were also found to efficiently inactivate cell-free HCV viral particles and impede viral attachment. Another natural compound curcumin extracted from turmeric was shown to decrease the fluidity of viral envelope and therefore prevent the binding and fusion [107], possibly by inserting into the membrane in a manner similar to cholesterol [108].…”