A novel small molecule inhibitor of hepatitis C virus entry.

Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful...

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Autores principales:	Carl J Baldick, Michael J Wichroski, Annapurna Pendri, Ann W Walsh, Jie Fang, Charles E Mazzucco, Kevin A Pokornowski, Ronald E Rose, Betsy J Eggers, Mayla Hsu, Weixu Zhai, Guangzhi Zhai, Samuel W Gerritz, Michael A Poss, Nicholas A Meanwell, Mark I Cockett, Daniel J Tenney
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1ee8b0be7b894e5398d932dbcf2e4866
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spelling	oai:doaj.org-article:1ee8b0be7b894e5398d932dbcf2e48662021-11-18T06:01:39ZA novel small molecule inhibitor of hepatitis C virus entry.1553-73661553-737410.1371/journal.ppat.1001086https://doaj.org/article/1ee8b0be7b894e5398d932dbcf2e48662010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20838466/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.Carl J BaldickMichael J WichroskiAnnapurna PendriAnn W WalshJie FangCharles E MazzuccoKevin A PokornowskiRonald E RoseBetsy J EggersMayla HsuWeixu ZhaiGuangzhi ZhaiSamuel W GerritzMichael A PossNicholas A MeanwellMark I CockettDaniel J TenneyPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 9, p e1001086 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Carl J Baldick Michael J Wichroski Annapurna Pendri Ann W Walsh Jie Fang Charles E Mazzucco Kevin A Pokornowski Ronald E Rose Betsy J Eggers Mayla Hsu Weixu Zhai Guangzhi Zhai Samuel W Gerritz Michael A Poss Nicholas A Meanwell Mark I Cockett Daniel J Tenney A novel small molecule inhibitor of hepatitis C virus entry.
description	Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.
format	article
author	Carl J Baldick Michael J Wichroski Annapurna Pendri Ann W Walsh Jie Fang Charles E Mazzucco Kevin A Pokornowski Ronald E Rose Betsy J Eggers Mayla Hsu Weixu Zhai Guangzhi Zhai Samuel W Gerritz Michael A Poss Nicholas A Meanwell Mark I Cockett Daniel J Tenney
author_facet	Carl J Baldick Michael J Wichroski Annapurna Pendri Ann W Walsh Jie Fang Charles E Mazzucco Kevin A Pokornowski Ronald E Rose Betsy J Eggers Mayla Hsu Weixu Zhai Guangzhi Zhai Samuel W Gerritz Michael A Poss Nicholas A Meanwell Mark I Cockett Daniel J Tenney
author_sort	Carl J Baldick
title	A novel small molecule inhibitor of hepatitis C virus entry.
title_short	A novel small molecule inhibitor of hepatitis C virus entry.
title_full	A novel small molecule inhibitor of hepatitis C virus entry.
title_fullStr	A novel small molecule inhibitor of hepatitis C virus entry.
title_full_unstemmed	A novel small molecule inhibitor of hepatitis C virus entry.
title_sort	novel small molecule inhibitor of hepatitis c virus entry.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/1ee8b0be7b894e5398d932dbcf2e4866
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A novel small molecule inhibitor of hepatitis C virus entry.

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