High potency of indolyl aryl sulfone nonnucleoside inhibitors towards drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutants is due to selective targeting of different mechanistic forms of the enzyme
Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.
| 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), 11 vom: 08. Nov., Seite 4546-54 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cancio, Reynel [VerfasserIn] |
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| Themen: |
EC 2.7.7.49 |
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| Anmerkungen: |
Date Completed 18.01.2006 Date Revised 13.11.2018 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM158599225 |
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| 100 | 1 | |a Cancio, Reynel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a High potency of indolyl aryl sulfone nonnucleoside inhibitors towards drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutants is due to selective targeting of different mechanistic forms of the enzyme |
| 264 | 1 | |c 2005 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 18.01.2006 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
| 650 | 7 | |a Sulfones |2 NLM | |
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| 700 | 1 | |a Silvestri, Romano |e verfasserin |4 aut | |
| 700 | 1 | |a Ragno, Rino |e verfasserin |4 aut | |
| 700 | 1 | |a Artico, Marino |e verfasserin |4 aut | |
| 700 | 1 | |a De Martino, Gabriella |e verfasserin |4 aut | |
| 700 | 1 | |a La Regina, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a Crespan, Emmanuele |e verfasserin |4 aut | |
| 700 | 1 | |a Zanoli, Samantha |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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