scholarly journals Critical Effect of the Detergent:Protein Ratio on the Formation of the Hepatitis C Virus p7 Channel

Biochemistry ◽  
2019 ◽  
Vol 58 (37) ◽  
pp. 3834-3837 ◽  
Author(s):  
Wen Chen ◽  
Bo OuYang ◽  
James J. Chou
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Critical Effect ◽  
P7 Channel

scholarly journals Determinants of Hepatitis C Virus p7 Ion Channel Function and Drug Sensitivity Identified In Vitro

2009 ◽  
Vol 83 (16) ◽  
pp. 7970-7981 ◽  
Author(s):  
Corine StGelais ◽  
Toshana L. Foster ◽  
Mark Verow ◽  
Elizabeth Atkins ◽  
Colin W. G. Fishwick ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Ion Channel ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Channel Activity ◽  
Amino Terminal ◽  
Channel Function ◽  
P7 Channel

ABSTRACT Hepatitis C virus (HCV) chronically infects 170 million individuals, causing severe liver disease. Although antiviral chemotherapy exists, the current regimen is ineffective in 50% of cases due to high levels of innate virus resistance. New, virus-specific therapies are forthcoming although their development has been slow and they are few in number, driving the search for new drug targets. The HCV p7 protein forms an ion channel in vitro and is critical for the secretion of infectious virus. p7 displays sensitivity to several classes of compounds, making it an attractive drug target. We recently demonstrated that p7 compound sensitivity varies according to viral genotype, yet little is known of the residues within p7 responsible for channel activity or drug interactions. Here, we have employed a liposome-based assay for p7 channel function to investigate the genetic basis for compound sensitivity. We demonstrate using chimeric p7 proteins that neither the two trans-membrane helices nor the p7 basic loop individually determines compound sensitivity. Using point mutation analysis, we identify amino acids important for channel function and demonstrate that null mutants exert a dominant negative effect over wild-type protein. We show that, of the three hydrophilic regions within the amino-terminal trans-membrane helix, only the conserved histidine at position 17 is important for genotype 1b p7 channel activity. Mutations predicted to play a structural role affect both channel function and oligomerization kinetics. Lastly, we identify a region at the p7 carboxy terminus which may act as a specific sensitivity determinant for the drug amantadine.

scholarly journals Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Joseph Shaw ◽  
Rajendra Gosain ◽  
Monoj Mon Kalita ◽  
Toshana L Foster ◽  
Jayakanth Kankanala ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Discovery ◽  
Influenza A ◽  
Proton Channel ◽  
Single Class ◽  
Modern Drug ◽  
The 1960S ◽  
Targeted Drug Discovery ◽  
P7 Channel

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

scholarly journals Unusual architecture of the p7 channel from hepatitis C virus

Nature ◽  
2013 ◽  
Vol 498 (7455) ◽  
pp. 521-525 ◽  
Author(s):  
Bo OuYang ◽  
Shiqi Xie ◽  
Marcelo J. Berardi ◽  
Xinhao Zhao ◽  
Jyoti Dev ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
P7 Channel

scholarly journals Author response: Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

2020 ◽  
Author(s):  
Joseph Shaw ◽  
Rajendra Gosain ◽  
Monoj Mon Kalita ◽  
Toshana L Foster ◽  
Jayakanth Kankanala ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Therapy ◽  
Author Response ◽  
Channel Activity ◽  
P7 Channel

scholarly journals Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

2018 ◽  
Author(s):  
Joseph Shaw ◽  
Rajendra Gosein ◽  
Monoj Mon Kalita ◽  
Toshana L. Foster ◽  
Jayakanth Kankanala ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Discovery ◽  
Influenza A ◽  
Proton Channel ◽  
Single Class ◽  
Modern Drug ◽  
The 1960S ◽  
Targeted Drug Discovery ◽  
P7 Channel

AbstractSince the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or “viroporins”, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery.We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

scholarly journals In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e93613 ◽  
Author(s):  
Qi-Shi Du ◽  
Shu-Qing Wang ◽  
Dong Chen ◽  
Jian-Zong Meng ◽  
Ri-Bo Huang
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Sites ◽  
Nmr Structure ◽  
Adamantane Derivatives ◽  
Depth Analysis ◽  
P7 Channel

scholarly journals Structural basis of interaction between the hepatitis C virus p7 channel and its blocker hexamethylene amiloride

2016 ◽  
Vol 7 (4) ◽  
pp. 300-304 ◽  
Author(s):  
Linlin Zhao ◽  
Shuqing Wang ◽  
Lingyu Du ◽  
Jyoti Dev ◽  
Liujuan Zhou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structural Basis ◽  
P7 Channel ◽  
Hexamethylene Amiloride

HEPATITIS C VIRUS INFECTION (AND ADDITIONAL NEOPLASMS) AMONG MARGINAL ZONE LYMPHOMAS

1997 ◽  
Vol 96 (2) ◽  
pp. 427-428 ◽  
Author(s):  
FREDERICO SILVESTRI ◽  
GIOVANNI BARILLARI ◽  
RENATO FANIN ◽  
FLAVIA SALMASO ◽  
LAURA INFANTI ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Marginal Zone ◽  
Hepatitis C Virus Infection
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