About: Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity

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An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity
Creator	Wakita, Takaji Watashi, Koichi Tanaka, Yasuhito Fukano, Kento Peel, Michael Mizokami, Masashi Iwamoto, Masashi Kusuhara, Hiroyuki Sluder, Ann Sugiyama, Masaya Tsukuda, Senko Kawai, Fumihiro Miyake, Takeshi Ogasawara, Yuki Park, Sam-Yong Shimura, Satomi Sureau, Camille Takeuchi, Junko
Source	Elsevier; Medline; PMC
abstract	BACKGROUND & AIMS: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. METHODS: We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. RESULTS: We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC(50). Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. CONCLUSIONS: This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. LAY SUMMARY: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.
has issue date	2016-11-25(xsd:dateTime)
bibo:doi	10.1016/j.jhep.2016.11.009
bibo:pmid	27890789
has license	no-cc
sha1sum (hex)	29d880d76f80084969dac74365c4a42febaeea43
schema:url	https://doi.org/10.1016/j.jhep.2016.11.009
resource representing a document's title	Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity
has PubMed Central identifier	PMC7172969
has PubMed identifier	27890789
schema:publication	J Hepatol
resource representing a document's body	covid:29d880d76f80084969dac74365c4a42febaeea43#body_text
is schema:about of	named entity 'functionally' named entity 'This' named entity 'hepatitis B virus' named entity 'broadly' named entity 'nucleoside' named entity 'HBV' named entity 'NTCP' named entity 'host cells' named entity 'coronaviruses' named entity 'bile acid' named entity 'HBV' named entity 'ritonavir' named entity 'cell surface' named entity 'life cycle' named entity 'HBV' named entity 'inhibitory activity' named entity 'multidrug' named entity 'host cells' named entity 'sodium' named entity 'adverse effects' named entity 'CsA' named entity 'HBV' named entity 'infection' named entity 'calcineurin' named entity 'bile acid' named entity 'NTCP' named entity 'mutation' named entity 'bile acid' named entity 'cell surface' named entity 'HBV' named entity 'NTCP' named entity 'NTCP' named entity 'CsA' named entity 'immunosuppressive' named entity 'RANTES' named entity 'bile acid' named entity 'reverse transcription' named entity 'Bile acid' named entity 'CCR5' named entity 'NTCP' named entity 'bile acid' named entity 'sodium taurocholate' named entity 'CsA' named entity 'CsA' named entity 'NTCP' named entity 'HBV' named entity 'HBV' named entity 'ASBT' named entity 'HBV' named entity 'infection' named entity 'CsA' named entity 'hepatocytes' named entity 'genotypes' named entity 'virions' named entity 'isomerase' named entity 'Maraviroc' named entity 'HBV' named entity 'receptor' named entity 'antiviral activity' named entity 'cyclophilin' named entity 'protein' named entity 'amino acid residues' named entity 'hepatitis B virus' named entity 'membrane transporter'

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