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Updated: Mar 17, 2026
Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds
Published on: October 29, 2015
(4R,6S)-2-Dihydromenisdaurilide is a Butenolide that Efficiently Inhibits Hepatitis C Virus Entry
Chueh-Yao Chung1, Ching-Hsuan Liu2, Guey-Horng Wang3
1Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Insights
A natural compound, (4R,6S)-2-dihydromenisdaurilide (DHMD), effectively inhibits hepatitis C virus (HCV) entry by targeting early infection stages. DHMD shows promise as a novel therapeutic for HCV, especially in liver transplant patients.
Area of Science:
- Virology
- Natural Product Chemistry
- Hepatology
Background:
- Hepatitis C virus (HCV) infection affects 170-300 million globally, risking cirrhosis and liver cancer.
- Current direct-acting antivirals face challenges like resistance, side effects, cost, and treating post-transplant reinfection.
- Novel therapeutics targeting viral entry are needed to broaden HCV treatment strategies.
Purpose of the Study:
- To identify and characterize novel inhibitors of HCV entry.
- To evaluate the potential of the natural butenolide (4R,6S)-2-dihydromenisdaurilide (DHMD) as an HCV entry inhibitor.
Main Methods:
- Assessed DHMD's antiviral activity against HCV infection in vitro.
- Examined DHMD's effect on the viral life cycle and its mechanism of action.
- Utilized ELISA and confocal microscopy to validate DHMD's impact on viral adsorption and entry.
Main Results:
- DHMD demonstrated potent, non-cytotoxic inhibition of HCV infection.
- DHMD selectively targeted early viral entry steps, including inactivation of cell-free virus, abrogation of attachment, and inhibition of entry/fusion.
- DHMD did not affect viral replication, assembly, release, or induce an interferon response.
Conclusions:
- DHMD is an effective inhibitor of HCV entry, primarily acting during viral adsorption.
- DHMD's unique mechanism and potency make it a promising candidate for developing new HCV therapeutics.
- DHMD holds potential value for treating HCV, particularly in liver transplant recipients.
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.
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