New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains
Copyright © 2020 Elsevier Masson SAS. All rights reserved..
We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N-Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N-Y181C RTs to binary and ternary complexes, respectively.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:208 |
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| Enthalten in: |
European journal of medicinal chemistry - 208(2020) vom: 15. Dez., Seite 112696 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nalli, Marianna [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.05.2021 Date Revised 26.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2020.112696 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N-Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N-Y181C RTs to binary and ternary complexes, respectively | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AIDS | |
| 650 | 4 | |a HIV-1 | |
| 650 | 4 | |a Indolylarylsulfone | |
| 650 | 4 | |a Non-nucleoside reverse transcriptase inhibitor | |
| 650 | 4 | |a Reverse transcriptase | |
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| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
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| 650 | 7 | |a reverse transcriptase, Human immunodeficiency virus 1 |2 NLM | |
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| 700 | 1 | |a Masci, Domiziana |e verfasserin |4 aut | |
| 700 | 1 | |a Coluccia, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Badia, Roger |e verfasserin |4 aut | |
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| 700 | 1 | |a Catalano, Myriam |e verfasserin |4 aut | |
| 700 | 1 | |a Limatola, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Esté, José A |e verfasserin |4 aut | |
| 700 | 1 | |a Maga, Giovanni |e verfasserin |4 aut | |
| 700 | 1 | |a Silvestri, Romano |e verfasserin |4 aut | |
| 700 | 1 | |a Crespan, Emmanuele |e verfasserin |4 aut | |
| 700 | 1 | |a La Regina, Giuseppe |e verfasserin |4 aut | |
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