Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation

Liu, Fengling; Kovalevsky, Andrey; Louis, John M.; Boross, Péter; Wang, Yuan‐Fang; Harrison, Robert W.; Weber, Irene T.

doi:10.1016/j.jmb.2006.02.076

Cited by 46 publications

(68 citation statements)

References 43 publications

(45 reference statements)

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“…5b), Ile59 50 and Ile63 54 could form reciprocal packing interactions between flaps, favoring a closed conformation [27]. Loss of an equivalent interaction results in a 6 Å separation between flaps in the Phe53Leu mutant of apo-HIV PR [28]. Two of the flap residues replaced in 12X FIV PR (Asn55 46 Met, Lys63 54 Ile) are also sites of mutation in the 'wide-open' conformation of a multidrug-resistant HIV PR [29].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

et al. 2007

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“…These mutations may also show reduced catalytic activity. (b) Mutations that alter the dimer interface show reduced dimer stability, such as I50V, L24I and F53L (Liu et al, , 2006. Mutations that disrupt the protease dimer are presumed to cause release of the drug without substantially reducing activity on the viral polyproteins so that infectious virus can be produced.…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

“…Mutations that disrupt the protease dimer are presumed to cause release of the drug without substantially reducing activity on the viral polyproteins so that infectious virus can be produced. The conformation and stability of the dimer are sensitive to mutations that alter intersubunit interactions in the presence or absence of inhibitor (Liu et al, 2006). Some mutations like I50V fall into both category (a) and (b).…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

“…Some mutants show different flap conformations in the absence or presence of substrate. A novel mechanism for resistance was suggested by the structure of unliganded mutant F53L, which altered the interactions between the two flaps in the open conformation (Liu et al, 2006). Another distinct mechanism of drug resistance was revealed by the structure of the I54V mutant with the tetrahedral reaction intermediate, which had lost water-mediated hydrogen bonds with the flap residues Ile50 and Ile50′ .…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

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HIV-1 Protease and AIDS Therapy

Weber

Zhang

Tőzsér

2009

Viral Proteases and Antiviral Protease Inhibitor Therapy

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Infection with HIV-1 causes the pandemic disease of AIDS in an estimated 30 million people. The viral protease has proved a successful target for AIDS therapy, and current effective therapy uses a selection from eight protease inhibitors in combination with other antiviral drugs. The antiviral protease inhibitors were developed over the past 15 years based on knowledge of the molecular structure of the protease, its substrate specificity and the mode of binding of inhibitors. Today, drug resistance has become a major challenge in AIDS therapy. Consequently, in the combat against drug resistance new antiviral protease inhibitors are being developed from structure-guided designs. These new drugs, such as darunavir, demonstrate high affinity binding to resistant mutants of HIV protease, and provide high genetic barriers to resistance. Recent developments are described in these structure-guided designs for antiviral therapy based on targeting the HIV-1 protease and its drug resistant mutants.

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“…Some experimental and computational studies have revealed that some active site mutations changed the direct interactions between protease and inhibitor and caused unfavorable contact between them [27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Some nonactive site mutations, for example L10F, F53L, and L90M, have also been reported to indirectly change the interactions between protease and inhibitor, leading to reduced binding affinities between them [29,32,[41][42][43][44][45]. Moreover, the currently available protease inhibitors are only active against the subtype B protease.…”

Section: Introductionmentioning

confidence: 99%

Drug-resistant molecular mechanism of CRF01_AE HIV-1 protease due to V82F mutation

Liu

Xiu

Hao

2009

J Comput Aided Mol Des

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Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the major targets of anti-AIDS drug discovery. The circulating recombinant form 01 A/E (CRF01_AE, abbreviated AE) subtype is one of the most common HIV-1 subtypes, which is infecting more humans and is expanding rapidly throughout the world. It is, therefore, necessary to develop inhibitors against subtype AE HIV-1 PR. In this work, we have performed computer simulation of subtype AE HIV-1 PR with the drugs lopinavir (LPV) and nelfinavir (NFV), and examined the mechanism of resistance of the V82F mutation of this protease against LPV both structurally and energetically. The V82F mutation at the active site results in a conformational change of 79's loop region and displacement of LPV from its proper binding site, and these changes lead to rotation of the side-chains of residues D25 and I50'. Consequently, the conformation of the binding cavity is deformed asymmetrically and some interactions between PR and LPV are destroyed. Additionally, by comparing the interactive mechanisms of LPV and NFV with HIV-1 PR we discovered that the presence of a dodecahydroisoquinoline ring at the P1' subsite, a [2-(2,6-dimethylphenoxy)acetyl]amino group at the P2' subsite, and an N2 atom at the P2 subsite could improve the binding affinity of the drug with AE HIV-1 PR. These findings are helpful for promising drug design.

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Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation

Cited by 46 publications

References 43 publications

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

HIV-1 Protease and AIDS Therapy

Drug-resistant molecular mechanism of CRF01_AE HIV-1 protease due to V82F mutation

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