Potent and Specific Inhibition of NTCP-Mediated HBV/HDV Infection and Substrate Transporting by a Novel, Oral-Available Cyclosporine A Analogue

Analogues of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analogue termed exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-01, Vol.64 (1), p.543-565
Main Authors: Liu, Yang, Ruan, Hanying, Li, Ying, Sun, Guoliang, Liu, Xiao, He, Wenhui, Mao, Fengfeng, He, Miaomiao, Yan, Liwei, Zhong, Guocai, Yan, Huan, Li, Wenhui, Zhang, Zhiyuan
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antiviral Agents - administration & dosage
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Cyclosporine - administration & dosage
Cyclosporine - pharmacology
Cyclosporine - therapeutic use
Drug Design
Drug Evaluation, Preclinical
Hep G2 Cells
Hepatitis B - drug therapy
Hepatitis B - physiopathology
Hepatitis D - drug therapy
Hepatitis D - physiopathology
Humans
Mice
Mice, Inbred C57BL
Organic Anion Transporters, Sodium-Dependent - physiology
Symporters - physiology
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Summary:Analogues of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analogue termed exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its cellular receptor NTCP, while it lacks immunosuppressive activity found in natural CsA. Intraperitoneal injection or oral intake of protects HDV-susceptible mouse model from HDV infection. serves as a promising lead for the development of novel anti-HDV/HBV agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01484