Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within...
| Main Authors: | , , , , , |
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| 格式: | Journal article |
| 語言: | English |
| 出版: |
2000
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| _version_ | 1826258902559227904 |
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| author | Ren, J Milton, J Weaver, K Short, SA Stuart, D Stammers, D |
| author_facet | Ren, J Milton, J Weaver, K Short, SA Stuart, D Stammers, D |
| author_sort | Ren, J |
| collection | OXFORD |
| description | BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency. |
| first_indexed | 2024-03-06T18:41:22Z |
| format | Journal article |
| id | oxford-uuid:0cf86b7b-4cd3-4b92-aa59-f74b1d163535 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:41:22Z |
| publishDate | 2000 |
| record_format | dspace |
| spelling | oxford-uuid:0cf86b7b-4cd3-4b92-aa59-f74b1d1635352022-03-26T09:38:06ZStructural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0cf86b7b-4cd3-4b92-aa59-f74b1d163535EnglishSymplectic Elements at Oxford2000Ren, JMilton, JWeaver, KShort, SAStuart, DStammers, D BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency. |
| spellingShingle | Ren, J Milton, J Weaver, K Short, SA Stuart, D Stammers, D Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title | Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title_full | Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title_fullStr | Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title_full_unstemmed | Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title_short | Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. |
| title_sort | structural basis for the resilience of efavirenz dmp 266 to drug resistance mutations in hiv 1 reverse transcriptase |
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