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Research ArticleArticle

The Role of Thr139 in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Sensitivity to (+)-Calanolide A

Joeri Auwerx, Fátima Rodríguez-Barrios, Francesca Ceccherini-Silberstein, Ana San-Félix, Sonsoles Velázquez, Erik De Clercq, María-José Camarasa, Carlo-Federico Perno, Federico Gago and Jan Balzarini
Molecular Pharmacology September 2005, 68 (3) 652-659; DOI: https://doi.org/10.1124/mol.105.012351
Joeri Auwerx
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Fátima Rodríguez-Barrios
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Francesca Ceccherini-Silberstein
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Ana San-Félix
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Sonsoles Velázquez
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Erik De Clercq
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María-José Camarasa
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Carlo-Federico Perno
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Federico Gago
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Jan Balzarini
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Abstract

The coumarins represent a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that were isolated from tropical plants. (+)-Calanolide A, the most potent compound of this class, selects for the T139I resistance mutation in HIV-1 reverse transcriptase (RT). Seven RTs mutated at amino acid position 139 (Ala, Lys, Tyr, Asp, Ile, Ser, and Gln) were constructed by site-directed mutagenesis. The mutant T139Q enzyme retained full catalytic activity compared with wild-type RT, whereas the mutant T139I, T139S, and T139A RTs retained only 85 to 50% of the activity. Mutant T139K, T139D, and T139Y RTs had seriously impaired catalytic activities. The mutations in the T139I and T139D RTs were shown to destabilize the RT heterodimer. (+)-Calanolide A lost inhibitory activity (up to 20-fold) against the mutant T139Y, T139Q, T139K, and T139I enzymes. All of the mutant enzymes retained marked susceptibility toward the other NNRTIs, including nevirapine, delavirdine, efavirenz, thiocarboxanilide UC-781, quinoxaline GW867420X, TSAO [[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide)] derivatives, and the nucleoside inhibitor, ddGTP. The fact that the T139I RT 1) proved to be resistant to (+)-calanolide A, 2) represents a catalytically efficient enzyme, and 3) requires only a single transition point mutation (ACA→ATA) in codon 139 seems to explain why mutant T139I RT virus strains, but not virus strains containing other amino acid changes at this position, predominantly emerge in cell cultures under (+)-calanolide A pressure.

  • Received February 25, 2005.
  • Accepted June 13, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (3)
Molecular Pharmacology
Vol. 68, Issue 3
1 Sep 2005
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Research ArticleArticle

The Role of Thr139 in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Sensitivity to (+)-Calanolide A

Joeri Auwerx, Fátima Rodríguez-Barrios, Francesca Ceccherini-Silberstein, Ana San-Félix, Sonsoles Velázquez, Erik De Clercq, María-José Camarasa, Carlo-Federico Perno, Federico Gago and Jan Balzarini
Molecular Pharmacology September 1, 2005, 68 (3) 652-659; DOI: https://doi.org/10.1124/mol.105.012351

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Research ArticleArticle

The Role of Thr139 in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Sensitivity to (+)-Calanolide A

Joeri Auwerx, Fátima Rodríguez-Barrios, Francesca Ceccherini-Silberstein, Ana San-Félix, Sonsoles Velázquez, Erik De Clercq, María-José Camarasa, Carlo-Federico Perno, Federico Gago and Jan Balzarini
Molecular Pharmacology September 1, 2005, 68 (3) 652-659; DOI: https://doi.org/10.1124/mol.105.012351
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