Drug resistance mutations in the nucleotide binding pocket of human immunodeficiency virus type 1 reverse transcriptase differentially affect the phosphorolysis-dependent primer unblocking activity in the presence of stavudine and zidovudine and its inhibition by efavirenz
Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) derivatives with D113E, Y115F, F116Y, Q151E/N, and M184V mutations were studied for their phosphorolysis-mediated resistance to the nucleoside RT inhibitors (NRTIs) zidovudine and stavudine and for their inhibition by the nonnucleoside analogs (NNRTIs) efavirenz and nevirapine. The results presented here indicate that these single amino acid substitutions within the nucleotide binding pocket of the viral RT can independently affect different enzymatic properties, such as catalytic efficiency, drug binding, and phosphorolytic activity. Moreover, small local alterations of the physicochemical properties of the microenvironment around the active site can have profound effects on some NRTIs while hardly affecting other ones. In conclusion, even though different mutations within the nucleotide binding pocket of HIV-1 RT can result in a common phenotype (i.e., drug resistance), the molecular mechanisms underlying this phenotype can be very different. Moreover, the same mutation can give rise to different phenotypes depending on the nature of the substrates and/or inhibitors.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2005 |
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| Erschienen: |
2005 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 49(2005), 1 vom: 23. Jan., Seite 342-9 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Crespan, Emmanuele [VerfasserIn] |
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| Anmerkungen: |
Date Completed 22.02.2005 Date Revised 09.12.2020 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM152788735 |
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| 100 | 1 | |a Crespan, Emmanuele |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Drug resistance mutations in the nucleotide binding pocket of human immunodeficiency virus type 1 reverse transcriptase differentially affect the phosphorolysis-dependent primer unblocking activity in the presence of stavudine and zidovudine and its inhibition by efavirenz |
| 264 | 1 | |c 2005 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 22.02.2005 | ||
| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) derivatives with D113E, Y115F, F116Y, Q151E/N, and M184V mutations were studied for their phosphorolysis-mediated resistance to the nucleoside RT inhibitors (NRTIs) zidovudine and stavudine and for their inhibition by the nonnucleoside analogs (NNRTIs) efavirenz and nevirapine. The results presented here indicate that these single amino acid substitutions within the nucleotide binding pocket of the viral RT can independently affect different enzymatic properties, such as catalytic efficiency, drug binding, and phosphorolytic activity. Moreover, small local alterations of the physicochemical properties of the microenvironment around the active site can have profound effects on some NRTIs while hardly affecting other ones. In conclusion, even though different mutations within the nucleotide binding pocket of HIV-1 RT can result in a common phenotype (i.e., drug resistance), the molecular mechanisms underlying this phenotype can be very different. Moreover, the same mutation can give rise to different phenotypes depending on the nature of the substrates and/or inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Alkynes |2 NLM | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a Benzoxazines |2 NLM | |
| 650 | 7 | |a Cyclopropanes |2 NLM | |
| 650 | 7 | |a Nucleotides |2 NLM | |
| 650 | 7 | |a Oxazines |2 NLM | |
| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
| 650 | 7 | |a Zidovudine |2 NLM | |
| 650 | 7 | |a 4B9XT59T7S |2 NLM | |
| 650 | 7 | |a Stavudine |2 NLM | |
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| 650 | 7 | |a HIV Reverse Transcriptase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.49 |2 NLM | |
| 650 | 7 | |a efavirenz |2 NLM | |
| 650 | 7 | |a JE6H2O27P8 |2 NLM | |
| 700 | 1 | |a Locatelli, Giada A |e verfasserin |4 aut | |
| 700 | 1 | |a Cancio, Reynel |e verfasserin |4 aut | |
| 700 | 1 | |a Hübscher, Ulrich |e verfasserin |4 aut | |
| 700 | 1 | |a Spadari, Silvio |e verfasserin |4 aut | |
| 700 | 1 | |a Maga, Giovanni |e verfasserin |4 aut | |
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