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ABSTRACT: The HIV-1 genome encodes an essential protease enzyme which is one of the major targets of antiviral therapy (1-3). Protease
inhibitors (PIs) have been proven to be potent antiviral agents and their introduction in 1995 led to the era of highly active
antiretroviral therapy, the most potent and prescribed treatment of HIV infections today (4, 5). Although resistance to HIV-1
reverse transcriptase inhibitors had been described in the late 1980s (6), it was originally thought that PIs would be much
less prone to drug evasion because of intrinsic genetic and structural constraints. Contrary to these expectations however,
a substantial number of patients in the initial studies with PIs experienced drug failure due to the accumulation of multiple
mutations in the HIV-1 protease gene (7-15). To understand the mechanisms leading to PI resistance better, it is important
to fi rst briefl y review the general structure of the enzyme as well as the interactions involved in inhibitor binding.
12/2008: pages 477-492;
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Alexandre Gagnon,
Ma'an H Amad,
Pierre R Bonneau,
René Coulombe,
Patrick L DeRoy, Louise Doyon,
Jianmin Duan,
Michel Garneau,
Ingrid Guse,
Araz Jakalian,
Eric Jolicoeur,
Serge Landry,
Eric Malenfant,
Bruno Simoneau,
Christiane Yoakim
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ABSTRACT: A series of aryl thiotetrazolylacetanilides were synthesized and found to be potent inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. The incorporation of an alkynyl fragment on the aniline provided inhibitors with excellent cellular activity and extensive SAR led to the identification of one inhibitor having good oral bioavailability in rats.
Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4437-41. · 2.55 Impact Factor
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ABSTRACT: Tipranavir is a novel, non-peptidic protease inhibitor, which possesses broad antiviral activity against multiple protease inhibitor-resistant HIV-1. Resistance to this inhibitor however has not yet been well described. HIV was passaged for 9 months in culture in the presence of tipranavir to select HIV with a drug-resistant phenotype. Characterization of the selected variants revealed that the first mutations to be selected were L33F and I84V in the viral protease, mutations which together conferred less than two-fold resistance to tipranavir. At the end of the selection experiments, viruses harbouring 10 mutations in the protease (L10F, I13V, V32I, L33F, M36I, K45I, I54V, A71V, V82L, I84V) as well as a mutation in the CA/SP1 gag cleavage site were selected and showed 87-fold decreased susceptibility to tipranavir. In vitro, tipranavir-resistant viruses had a reduced replicative capacity which could not be improved by the introduction of the CA/SP1 cleavage site mutation. Tipranavir resistant viruses showed cross-resistance to other currently approved protease inhibitors with the exception of saquinavir. These results demonstrate that the tipranavir resistance phenotype is associated with complex genotypic changes in the protease. Resistance necessitates the sequential accumulation of multiple mutations.
Antiviral Research 11/2005; 68(1):27-35. · 4.30 Impact Factor
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Jeff A O'Meara,
Christiane Yoakim,
Pierre R Bonneau,
Michael Bös,
Michael G Cordingley,
Robert Déziel, Louise Doyon,
Jianmin Duan,
Michel Garneau,
Ingrid Guse,
Serge Landry,
Eric Malenfant,
Julie Naud,
William W Ogilvie,
Bounkham Thavonekham,
Bruno Simoneau
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ABSTRACT: A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Journal of Medicinal Chemistry 09/2005; 48(17):5580-8. · 5.25 Impact Factor
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Peter W White,
Steve Titolo,
Karine Brault,
Louise Thauvette,
Alex Pelletier,
Ewald Welchner,
Lise Bourgon, Louise Doyon,
William W Ogilvie,
Christiane Yoakim,
Michael G Cordingley,
Jacques Archambault
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ABSTRACT: Human papillomavirus (HPV) DNA replication is initiated by recruitment of the E1 helicase by the E2 protein to the viral origin. Screening of our corporate compound collection with an assay measuring the cooperative binding of E1 and E2 to the origin identified a class of small molecule inhibitors of the protein interaction between E1 and E2. Isothermal titration calorimetry and changes in protein fluorescence showed that the inhibitors bind to the transactivation domain of E2, the region that interacts with E1. These compounds inhibit E2 of the low risk HPV types 6 and 11 but not those of high risk HPV types or of cottontail rabbit papillomavirus. Functional evidence that the transactivation domain is the target of inhibition was obtained by swapping this domain between a sensitive (HPV11) and a resistant (cottontail rabbit papillomavirus) E2 type and by identifying an amino acid substitution, E100A, that increases inhibition by approximately 10-fold. This class of inhibitors was found to antagonize specifically the E1-E2 interaction in vivo and to inhibit HPV DNA replication in transiently transfected cells. These results highlight the potential of the E1-E2 interaction as a small molecule antiviral target.
Journal of Biological Chemistry 08/2003; 278(29):26765-72. · 4.77 Impact Factor
