Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A
The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance in vitro and in a mou...
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| Veröffentlicht in: | Nature (London) 2015-11, Vol.527 (7577), p.245-248 |
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| creator | Sun, Jin-Hua O’Boyle II, Donald R. Fridell, Robert A. Langley, David R. Wang, Chunfu Roberts, Susan B. Nower, Peter Johnson, Benjamin M. Moulin, Frederic Nophsker, Michelle J. Wang, Ying-Kai Liu, Mengping Rigat, Karen Tu, Yong Hewawasam, Piyasena Kadow, John Meanwell, Nicholas A. Cockett, Mark Lemm, Julie A. Kramer, Melissa Belema, Makonen Gao, Min |
| description | The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance
in vitro
and in a mouse model.
Mechanism of action of NS5A inhibitors in hepatitis C
The recently approved drug daclatasivir can successfully reduce viral load in patients infected with hepatitis C virus (HCV) by inhibiting the virus's non-structural protein 5A (NS5A) replication complex, although HCV NS5A inhibitor resistance mutations arise in some cases. Min Gao and colleagues now show that a combination of daclatasivir and an NS5A analogue can enhance daclatasivir potency, and the combination also overcomes resistance
in vitro
and in a mouse model. The authors develop a model to explain this effect, whereby inhibitor binding to one resistant NS5A causes a conformational change that is transmitted to adjacent NS5A molecules, restoring drug sensitivity to the resistant molecules.
It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide
1
,
2
. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents
3
. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle
4
. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with
in vitro
activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed
in vitro
has translated into clinical efficacy, with HCV RNA declining by ~3–4 log
10
in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated
in vivo
using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor bi |
| doi_str_mv | 10.1038/nature15711 |
| format | Article |
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in vitro
and in a mouse model.
Mechanism of action of NS5A inhibitors in hepatitis C
The recently approved drug daclatasivir can successfully reduce viral load in patients infected with hepatitis C virus (HCV) by inhibiting the virus's non-structural protein 5A (NS5A) replication complex, although HCV NS5A inhibitor resistance mutations arise in some cases. Min Gao and colleagues now show that a combination of daclatasivir and an NS5A analogue can enhance daclatasivir potency, and the combination also overcomes resistance
in vitro
and in a mouse model. The authors develop a model to explain this effect, whereby inhibitor binding to one resistant NS5A causes a conformational change that is transmitted to adjacent NS5A molecules, restoring drug sensitivity to the resistant molecules.
It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide
1
,
2
. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents
3
. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle
4
. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with
in vitro
activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed
in vitro
has translated into clinical efficacy, with HCV RNA declining by ~3–4 log
10
in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated
in vivo
using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature15711</identifier><identifier>PMID: 26536115</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 38/23 ; 631/154/436 ; 631/326/596/1905 ; 631/92/609 ; 64/60 ; 82/1 ; 82/83 ; Allosteric Regulation - drug effects ; Animals ; Antiviral Agents - pharmacology ; Binding sites ; Biphenyl Compounds - pharmacology ; Carbamates ; Cell Line ; Drug resistance ; Drug Resistance, Viral - drug effects ; Drug sensitization ; Drug Synergism ; Drug therapy ; Drug Therapy, Combination ; Health aspects ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepacivirus - metabolism ; Hepatitis ; Hepatitis C ; Hepatitis C - virology ; Hepatocytes - transplantation ; Humanities and Social Sciences ; Humans ; Imidazoles - pharmacology ; letter ; Methods ; Mice ; Models, Molecular ; multidisciplinary ; Phosphoproteins ; Protein Conformation - drug effects ; Protein Multimerization - drug effects ; Protein Structure, Quaternary - drug effects ; Proteins ; Pyrrolidines ; Reproducibility of Results ; Science ; Studies ; Synergistic effect ; Valine - analogs & derivatives ; Viral diseases ; Viral Nonstructural Proteins - chemistry ; Viral Nonstructural Proteins - genetics ; Viral Nonstructural Proteins - metabolism ; Virus Replication - drug effects</subject><ispartof>Nature (London), 2015-11, Vol.527 (7577), p.245-248</ispartof><rights>Springer Nature Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 12, 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-29e73b48086c9651a53467becbf1d26041dafde5f51c6aba78e9b5aa5631befa3</citedby><cites>FETCH-LOGICAL-c556t-29e73b48086c9651a53467becbf1d26041dafde5f51c6aba78e9b5aa5631befa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature15711$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature15711$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26536115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Jin-Hua</creatorcontrib><creatorcontrib>O’Boyle II, Donald R.</creatorcontrib><creatorcontrib>Fridell, Robert A.</creatorcontrib><creatorcontrib>Langley, David R.</creatorcontrib><creatorcontrib>Wang, Chunfu</creatorcontrib><creatorcontrib>Roberts, Susan B.</creatorcontrib><creatorcontrib>Nower, Peter</creatorcontrib><creatorcontrib>Johnson, Benjamin M.</creatorcontrib><creatorcontrib>Moulin, Frederic</creatorcontrib><creatorcontrib>Nophsker, Michelle J.</creatorcontrib><creatorcontrib>Wang, Ying-Kai</creatorcontrib><creatorcontrib>Liu, Mengping</creatorcontrib><creatorcontrib>Rigat, Karen</creatorcontrib><creatorcontrib>Tu, Yong</creatorcontrib><creatorcontrib>Hewawasam, Piyasena</creatorcontrib><creatorcontrib>Kadow, John</creatorcontrib><creatorcontrib>Meanwell, Nicholas A.</creatorcontrib><creatorcontrib>Cockett, Mark</creatorcontrib><creatorcontrib>Lemm, Julie A.</creatorcontrib><creatorcontrib>Kramer, Melissa</creatorcontrib><creatorcontrib>Belema, Makonen</creatorcontrib><creatorcontrib>Gao, Min</creatorcontrib><title>Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance
in vitro
and in a mouse model.
Mechanism of action of NS5A inhibitors in hepatitis C
The recently approved drug daclatasivir can successfully reduce viral load in patients infected with hepatitis C virus (HCV) by inhibiting the virus's non-structural protein 5A (NS5A) replication complex, although HCV NS5A inhibitor resistance mutations arise in some cases. Min Gao and colleagues now show that a combination of daclatasivir and an NS5A analogue can enhance daclatasivir potency, and the combination also overcomes resistance
in vitro
and in a mouse model. The authors develop a model to explain this effect, whereby inhibitor binding to one resistant NS5A causes a conformational change that is transmitted to adjacent NS5A molecules, restoring drug sensitivity to the resistant molecules.
It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide
1
,
2
. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents
3
. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle
4
. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with
in vitro
activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed
in vitro
has translated into clinical efficacy, with HCV RNA declining by ~3–4 log
10
in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated
in vivo
using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.</description><subject>13</subject><subject>13/106</subject><subject>38/23</subject><subject>631/154/436</subject><subject>631/326/596/1905</subject><subject>631/92/609</subject><subject>64/60</subject><subject>82/1</subject><subject>82/83</subject><subject>Allosteric Regulation - drug effects</subject><subject>Animals</subject><subject>Antiviral Agents - pharmacology</subject><subject>Binding sites</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Carbamates</subject><subject>Cell Line</subject><subject>Drug resistance</subject><subject>Drug Resistance, Viral - drug effects</subject><subject>Drug sensitization</subject><subject>Drug Synergism</subject><subject>Drug therapy</subject><subject>Drug Therapy, Combination</subject><subject>Health aspects</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepacivirus - metabolism</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C - virology</subject><subject>Hepatocytes - transplantation</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>letter</subject><subject>Methods</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>multidisciplinary</subject><subject>Phosphoproteins</subject><subject>Protein Conformation - drug effects</subject><subject>Protein Multimerization - drug effects</subject><subject>Protein Structure, Quaternary - drug effects</subject><subject>Proteins</subject><subject>Pyrrolidines</subject><subject>Reproducibility of Results</subject><subject>Science</subject><subject>Studies</subject><subject>Synergistic effect</subject><subject>Valine - analogs & derivatives</subject><subject>Viral diseases</subject><subject>Viral Nonstructural Proteins - chemistry</subject><subject>Viral Nonstructural Proteins - genetics</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Virus Replication - drug 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daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A</title><author>Sun, Jin-Hua ; O’Boyle II, Donald R. ; Fridell, Robert A. ; Langley, David R. ; Wang, Chunfu ; Roberts, Susan B. ; Nower, Peter ; Johnson, Benjamin M. ; Moulin, Frederic ; Nophsker, Michelle J. ; Wang, Ying-Kai ; Liu, Mengping ; Rigat, Karen ; Tu, Yong ; Hewawasam, Piyasena ; Kadow, John ; Meanwell, Nicholas A. ; Cockett, Mark ; Lemm, Julie A. ; Kramer, Melissa ; Belema, Makonen ; Gao, Min</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c556t-29e73b48086c9651a53467becbf1d26041dafde5f51c6aba78e9b5aa5631befa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13</topic><topic>13/106</topic><topic>38/23</topic><topic>631/154/436</topic><topic>631/326/596/1905</topic><topic>631/92/609</topic><topic>64/60</topic><topic>82/1</topic><topic>82/83</topic><topic>Allosteric Regulation - drug 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C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Jin-Hua</au><au>O’Boyle II, Donald R.</au><au>Fridell, Robert A.</au><au>Langley, David R.</au><au>Wang, Chunfu</au><au>Roberts, Susan B.</au><au>Nower, Peter</au><au>Johnson, Benjamin M.</au><au>Moulin, Frederic</au><au>Nophsker, Michelle J.</au><au>Wang, Ying-Kai</au><au>Liu, Mengping</au><au>Rigat, Karen</au><au>Tu, Yong</au><au>Hewawasam, Piyasena</au><au>Kadow, John</au><au>Meanwell, Nicholas A.</au><au>Cockett, Mark</au><au>Lemm, Julie A.</au><au>Kramer, Melissa</au><au>Belema, Makonen</au><au>Gao, Min</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2015-11-12</date><risdate>2015</risdate><volume>527</volume><issue>7577</issue><spage>245</spage><epage>248</epage><pages>245-248</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance
in vitro
and in a mouse model.
Mechanism of action of NS5A inhibitors in hepatitis C
The recently approved drug daclatasivir can successfully reduce viral load in patients infected with hepatitis C virus (HCV) by inhibiting the virus's non-structural protein 5A (NS5A) replication complex, although HCV NS5A inhibitor resistance mutations arise in some cases. Min Gao and colleagues now show that a combination of daclatasivir and an NS5A analogue can enhance daclatasivir potency, and the combination also overcomes resistance
in vitro
and in a mouse model. The authors develop a model to explain this effect, whereby inhibitor binding to one resistant NS5A causes a conformational change that is transmitted to adjacent NS5A molecules, restoring drug sensitivity to the resistant molecules.
It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide
1
,
2
. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents
3
. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle
4
. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with
in vitro
activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed
in vitro
has translated into clinical efficacy, with HCV RNA declining by ~3–4 log
10
in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated
in vivo
using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26536115</pmid><doi>10.1038/nature15711</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2015-11, Vol.527 (7577), p.245-248 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_journals_1733897467 |
| source | MEDLINE; Nature; Springer Nature - Complete Springer Journals |
| subjects | 13 13/106 38/23 631/154/436 631/326/596/1905 631/92/609 64/60 82/1 82/83 Allosteric Regulation - drug effects Animals Antiviral Agents - pharmacology Binding sites Biphenyl Compounds - pharmacology Carbamates Cell Line Drug resistance Drug Resistance, Viral - drug effects Drug sensitization Drug Synergism Drug therapy Drug Therapy, Combination Health aspects Hepacivirus - drug effects Hepacivirus - genetics Hepacivirus - metabolism Hepatitis Hepatitis C Hepatitis C - virology Hepatocytes - transplantation Humanities and Social Sciences Humans Imidazoles - pharmacology letter Methods Mice Models, Molecular multidisciplinary Phosphoproteins Protein Conformation - drug effects Protein Multimerization - drug effects Protein Structure, Quaternary - drug effects Proteins Pyrrolidines Reproducibility of Results Science Studies Synergistic effect Valine - analogs & derivatives Viral diseases Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - metabolism Virus Replication - drug effects |
| title | Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A |
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