Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent.
Ledipasvir, a direct acting antiviral agent (DAA) targeting the Hepatitis C Virus NS5A protein, exhibits picomolar activity in replicon cells. While its mechanism of action is unclear, mutations that confer resistance to ledipasvir in HCV replicon cells are located in NS5A, suggesting that NS5A is t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4391872?pdf=render |
| _version_ | 1818881179123712000 |
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| author | Hyock Joo Kwon Weimei Xing Katie Chan Anita Niedziela-Majka Katherine M Brendza Thorsten Kirschberg Darryl Kato John O Link Guofeng Cheng Xiaohong Liu Roman Sakowicz |
| author_facet | Hyock Joo Kwon Weimei Xing Katie Chan Anita Niedziela-Majka Katherine M Brendza Thorsten Kirschberg Darryl Kato John O Link Guofeng Cheng Xiaohong Liu Roman Sakowicz |
| author_sort | Hyock Joo Kwon |
| collection | DOAJ |
| description | Ledipasvir, a direct acting antiviral agent (DAA) targeting the Hepatitis C Virus NS5A protein, exhibits picomolar activity in replicon cells. While its mechanism of action is unclear, mutations that confer resistance to ledipasvir in HCV replicon cells are located in NS5A, suggesting that NS5A is the direct target of ledipasvir. To date co-precipitation and cross-linking experiments in replicon or NS5A transfected cells have not conclusively shown a direct, specific interaction between NS5A and ledipasvir. Using recombinant, full length NS5A, we show that ledipasvir binds directly, with high affinity and specificity, to NS5A. Ledipasvir binding to recombinant NS5A is saturable with a dissociation constant in the low nanomolar range. A mutant form of NS5A (Y93H) that confers resistance to ledipasvir shows diminished binding to ledipasvir. The current study shows that ledipasvir inhibits NS5A through direct binding and that resistance to ledipasvir is the result of a reduction in binding affinity to NS5A mutants. |
| first_indexed | 2024-12-19T14:57:45Z |
| format | Article |
| id | doaj.art-2ec4378953f54de7b0076a7adeb703bd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T14:57:45Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2ec4378953f54de7b0076a7adeb703bd2022-12-21T20:16:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012284410.1371/journal.pone.0122844Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent.Hyock Joo KwonWeimei XingKatie ChanAnita Niedziela-MajkaKatherine M BrendzaThorsten KirschbergDarryl KatoJohn O LinkGuofeng ChengXiaohong LiuRoman SakowiczLedipasvir, a direct acting antiviral agent (DAA) targeting the Hepatitis C Virus NS5A protein, exhibits picomolar activity in replicon cells. While its mechanism of action is unclear, mutations that confer resistance to ledipasvir in HCV replicon cells are located in NS5A, suggesting that NS5A is the direct target of ledipasvir. To date co-precipitation and cross-linking experiments in replicon or NS5A transfected cells have not conclusively shown a direct, specific interaction between NS5A and ledipasvir. Using recombinant, full length NS5A, we show that ledipasvir binds directly, with high affinity and specificity, to NS5A. Ledipasvir binding to recombinant NS5A is saturable with a dissociation constant in the low nanomolar range. A mutant form of NS5A (Y93H) that confers resistance to ledipasvir shows diminished binding to ledipasvir. The current study shows that ledipasvir inhibits NS5A through direct binding and that resistance to ledipasvir is the result of a reduction in binding affinity to NS5A mutants.http://europepmc.org/articles/PMC4391872?pdf=render |
| spellingShingle | Hyock Joo Kwon Weimei Xing Katie Chan Anita Niedziela-Majka Katherine M Brendza Thorsten Kirschberg Darryl Kato John O Link Guofeng Cheng Xiaohong Liu Roman Sakowicz Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. PLoS ONE |
| title | Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. |
| title_full | Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. |
| title_fullStr | Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. |
| title_full_unstemmed | Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. |
| title_short | Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. |
| title_sort | direct binding of ledipasvir to hcv ns5a mechanism of resistance to an hcv antiviral agent |
| url | http://europepmc.org/articles/PMC4391872?pdf=render |
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