Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

Abstract Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV...

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Autores principales:	Michael Kirstgen, Kira Alessandra Alicia Theresa Lowjaga, Simon Franz Müller, Nora Goldmann, Felix Lehmann, Sami Alakurtti, Jari Yli-Kauhaluoma, Dieter Glebe, Joachim Geyer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b5edf866c0b64b18948a6735dc0b00e5
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spelling	oai:doaj.org-article:b5edf866c0b64b18948a6735dc0b00e52021-12-02T12:33:15ZSelective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids10.1038/s41598-020-78618-22045-2322https://doaj.org/article/b5edf866c0b64b18948a6735dc0b00e52020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78618-2https://doaj.org/toc/2045-2322Abstract Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP’s physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure–activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.Michael KirstgenKira Alessandra Alicia Theresa LowjagaSimon Franz MüllerNora GoldmannFelix LehmannSami AlakurttiJari Yli-KauhaluomaDieter GlebeJoachim GeyerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael Kirstgen Kira Alessandra Alicia Theresa Lowjaga Simon Franz Müller Nora Goldmann Felix Lehmann Sami Alakurtti Jari Yli-Kauhaluoma Dieter Glebe Joachim Geyer Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
description	Abstract Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP’s physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure–activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.
format	article
author	Michael Kirstgen Kira Alessandra Alicia Theresa Lowjaga Simon Franz Müller Nora Goldmann Felix Lehmann Sami Alakurtti Jari Yli-Kauhaluoma Dieter Glebe Joachim Geyer
author_facet	Michael Kirstgen Kira Alessandra Alicia Theresa Lowjaga Simon Franz Müller Nora Goldmann Felix Lehmann Sami Alakurtti Jari Yli-Kauhaluoma Dieter Glebe Joachim Geyer
author_sort	Michael Kirstgen
title	Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
title_short	Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
title_full	Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
title_fullStr	Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
title_full_unstemmed	Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
title_sort	selective hepatitis b and d virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/b5edf866c0b64b18948a6735dc0b00e5
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Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

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