Analysis of HIV-1 CRF_01 A/E Protease Inhibitor Resistance:  Structural Determinants for Maintaining Sensitivity and Developing Resistance to Atazanavir

Clemente, José C.; Coman, Roxana M.; Thiaville, Michele M.; Janka, Linda K.; Jeung, Jennifer A.; Nukoolkarn, Sarawut; Govindasamy, Lakshmanan; Agbandje‐McKenna, Mavis; McKenna, Robert; Leelamanit, Wichet; Goodenow, Maureen M.; Dunn, Ben M.

doi:10.1021/bi051886s

Cited by 70 publications

(91 citation statements)

References 38 publications

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“…However, the potency loss was at least threefold less with atazanavir than with the other PIs. Moreover, the IC 50 values are consistent with those published in a study by Clemente et al (5) in which three pairs of ϮV82F PRTs were assayed for activity by chromogenic cleavage against all seven FDA-approved PIs. None of the ϮV82F PRTs contained any of the other three IRM substitutions.…”

Section: Discussionsupporting

confidence: 86%

“…3), despite the conformational differences at P1Ј. This alternative binding mode is consistent with the ϮV82F mutant activity reported by Clemente et al (5).…”

Section: Fig 3 Stereo Overlay Of the Crm (Monomersupporting

confidence: 90%

“…This work also highlights the ability of atazanavir to adopt a different but effective binding mode in direct response to the clinically relevant V82F mutation. This ability of atazanavir to adopt a different conformation in the presence of the V82F mutation bodes well for the clinical use of atazanavir as a component of highly active antiretroviral therapy against the AE strain of HIV, where this particular mutation is routinely found and against which Clemente et al (5) have shown that atazanavir, in comparison to all other PIs, remains potent in vitro.…”

Section: Discussionmentioning

confidence: 71%

“…The electron density for the refined CRM structure is indicative of an alternate atazanavir orientation (Fig. 2), much like that in 1HXB and 1C6Z for saquinavir, 1MUI for lopinavir, and 2AQU for atazanavir (5). Even though both the CRM and IRM proteins crystallized in the same space group with similar unit cell dimensions, their crystal packing is very different in terms of some key intermolecular contacts.…”

Section: Structure Of Hiv Prt In Complex With Atazanavirmentioning

confidence: 93%

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X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

Klei

Kish

Lin

et al. 2007

J Virol

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Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.The human immunodeficiency virus type 1 (HIV-1) protease (PRT) enzyme is essential for viral replication. As such, it is an attractive target for antiviral therapy. Indeed, a sustained, international effort of structure-based drug design has led to the development of potent HIV-1 PRT inhibitors (PIs) that bind to the active site of mature PRT. Several of these drugs are currently in use for the treatment of AIDS (18,31,36). The seven FDA-approved PIs currently on the market (in order of approval [http://www.fda.gov/oashi/aids/virals.html])-saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, and atazanavir-are competitive peptidomimetics (10,15). Unfortunately, the use of these PIs can lead to rapid selection for drug-resistant PRT variants (1,42,50). Mutations of the conserved PRT residues V82, I84, and L90 are among those most commonly observed in patients receiving PI-containing regimens. In addition, the collective data from clinical failures of antiviral therapy show considerable cross-resistance among the PIs (19). Both factors threaten the long-term effectiveness of these drugs. Therefore, it is important to understand the mechanisms that govern drug resistance in order to develop more effective inhibitors and to rationally formulate drug regimens.Atazanavir, a highly potent azapeptide, is the most recently approved HIV-1 PI. A favorable pharmacokinetic profile allows once-daily dosing (37,43,47). More importantly, atazanavir has a distinct resistance profile relative to those of the other approved PIs. Earlier in vitro studies demonstrated that the substitutions M46I, A71V, N88S, I84V, and I50L, which were identified in laboratory strains of PRT variants selected against atazanavir, may play important roles in the resistance phenotype and that multiple mutational pathways can lead to resistance (17). In clinical studies of treatment-experienced patients who received atazanavir-c...

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Section: Discussionsupporting

confidence: 86%

“…3), despite the conformational differences at P1Ј. This alternative binding mode is consistent with the ϮV82F mutant activity reported by Clemente et al (5).…”

Section: Fig 3 Stereo Overlay Of the Crm (Monomersupporting

confidence: 90%

Section: Discussionmentioning

confidence: 71%

Section: Structure Of Hiv Prt In Complex With Atazanavirmentioning

confidence: 93%

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X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

Klei

Kish

Lin

et al. 2007

J Virol

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“…These were modeled, and occupancies were adjusted until refined B-factors were similar for equivalent atoms. The presence of such alternative ligand orientations has been observed previously (5). Analyses were performed using the conformation refined with the highest occupancy as interactions between inhibitor and protease were similar between orientations.…”

Section: Methodsmentioning

confidence: 71%

Unique Thermodynamic Response of Tipranavir to Human Immunodeficiency Virus Type 1 Protease Drug Resistance Mutations

Muzammil

Armstrong

Kang

et al. 2007

J Virol

112

118

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Drug resistance is a major problem affecting the clinical efficacy of antiretroviral agents, including protease inhibitors, in the treatment of infection with human immunodeficiency virus type 1 (HIV-1)/AIDS. Consequently, the elucidation of the mechanisms by which HIV-1 protease inhibitors maintain antiviral activity in the presence of mutations is critical to the development of superior inhibitors. Tipranavir, a nonpeptidic HIV-1 protease inhibitor, has been recently approved for the treatment of HIV infection. Tipranavir inhibits wild-type protease with high potency (K i ‫؍‬ 19 pM) and demonstrates durable efficacy in the treatment of patients infected with HIV-1 strains containing multiple common mutations associated with resistance. The high potency of tipranavir results from a very large favorable entropy change (؊T⌬S ‫؍‬ ؊14.6 kcal/mol) combined with a favorable, albeit small, enthalpy change (⌬H ‫؍‬ ؊0.7 kcal/mol, 25°C). Characterization of tipranavir binding to wild-type protease, active site mutants I50V and V82F/I84V, the multidrug-resistant mutant L10I/ L33I/M46I/I54V/L63I/V82A/I84V/L90M, and the tipranavir in vitro-selected mutant I13V/V32L/L33F/K45I/ V82L/I84V was performed by isothermal titration calorimetry and crystallography. Thermodynamically, the good response of tipranavir arises from a unique behavior: it compensates for entropic losses by actual enthalpic gains or by sustaining minimal enthalpic losses when facing the mutants. The net result is a small loss in binding affinity. Structurally, tipranavir establishes a very strong hydrogen bond network with invariant regions of the protease, which is maintained with the mutants, including catalytic Asp25 and the backbone of Asp29, Asp30, Gly48 and Ile50. Moreover, tipranavir forms hydrogen bonds directly to Ile50, while all other inhibitors do so by being mediated by a water molecule.

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HIV‐1 Protease Inhibitors as Antiretroviral Agents

Gulnik

Afonina

Eissenstat

2009

Enzyme Inhibition in Drug Discovery and Development

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Analysis of HIV-1 CRF_01 A/E Protease Inhibitor Resistance: Structural Determinants for Maintaining Sensitivity and Developing Resistance to Atazanavir

Cited by 70 publications

References 38 publications

X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

Unique Thermodynamic Response of Tipranavir to Human Immunodeficiency Virus Type 1 Protease Drug Resistance Mutations

HIV‐1 Protease Inhibitors as Antiretroviral Agents

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