Thyroxine-derivatives of lipopeptides: bifunctional dimerization inhibitors of human immunodeficiency virus-1 protease

Dumond, Julien; Boggetto, Nicole; Schramm, Hans J.; Schramm, W.; Takahashi, Masayuki; Reboud‐Ravaux, Michèle

doi:10.1016/s0006-2952(02)01622-2

Cited by 24 publications

(37 citation statements)

References 28 publications

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“…Several groups, including our own, have developed peptides, peptide mimetics or lipopeptides that can disrupt the dimerization of HIV-1 PR [19,20,22,23,31,46–48]. These inhibitors have been shown to inhibit dimerization based primarily on the results on dimerization kinetics by Zhang et al [31].…”

Section: Discussionmentioning

confidence: 99%

Analysis and characterization of dimerization inhibition of a multi-drug-resistant Human Immunodeficiency Virus Type 1 protease using a novel size-exclusion chromatographic approach

Davis

Tebbs

Daniels

et al. 2009

Biochemical Journal

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Active-site inhibitors of HIV-1 PR (protease) block viral replication by preventing viral maturation. However, HIV-1 often develops resistance to active-site inhibitors through multiple mutations in PR and therefore recent efforts have focused on inhibiting PR dimerization as an alternative approach. Dimerization inhibitors have been identified using kinetic analysis, but additional characterization of the effect of these inhibitors on PR by physical methods has been difficult. In the present study, we identified a PRMDR (multi-drug-resistant HIV-1 PR) that was highly resistant to autoproteolysis. Using this PR and a novel size-exclusion chromatographic approach that incorporated fluorescence and MS detection, we were able to demonstrate inhibition of dimerization using P27 (peptide 27), a peptide dimerization inhibitor of PR previously identified on the basis of kinetic analysis. Incubation of PRMDR with P27, or other dimerization inhibitors, led to a dose- and time-dependent formation of PR monomers based on the change in elution time by size exclusion and its similar elution time to engineered forms of monomeric PR, namely PRT26A and glutathionylated PR. In contrast, incubation of PRMDR with a potent active-site inhibitor did not change the elution time for the PRMDR dimer. The monomeric PR induced by P27 had fluorescent characteristics which were consistent with unfolded PR. Structure–activity studies identified the active regions of P27 and experiments were performed to examine the effect of other dimerization inhibitors on PR. The present study is the first characterization of dimerization inhibition of PRMDR, a prime target for these inhibitors, using a novel size-exclusion chromatographic approach.

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Section: Discussionmentioning

confidence: 99%

Analysis and characterization of dimerization inhibition of a multi-drug-resistant Human Immunodeficiency Virus Type 1 protease using a novel size-exclusion chromatographic approach

Davis

Tebbs

Daniels

et al. 2009

Biochemical Journal

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“…Modification of the termini of an interfacial peptide by attachment of a lipophilic group and alkyl chains (e.g., palmitoyl) improves both the inhibitory capacity and the specificity [128,129]. Currently, the most potent lipopeptide inhibitors, containing the minimal peptide sequence Leu-Glu-Tyr modified on the N-terminus by palmitoyl, attained sub-nanomolar K i values for the in vitro inhibition of the wild type and drug-resistant mutant variants [130].…”

Section: Alternative Hiv Protease Inhibitors Targeting Functional Dommentioning

confidence: 99%

Current and Novel Inhibitors of HIV Protease

Pokorná

Machala

Řezáčová

et al. 2009

Viruses

100

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The design, development and clinical success of HIV protease inhibitors represent one of the most remarkable achievements of molecular medicine. This review describes all nine currently available FDA-approved protease inhibitors, discusses their pharmacokinetic properties, off-target activities, side-effects, and resistance profiles. The compounds in the various stages of clinical development are also introduced, as well as alternative approaches, aiming at other functional domains of HIV PR. The potential of these novel compounds to open new way to the rational drug design of human viruses is critically assessed.

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“…As pointed out earlier, this kind of inhibitor could be more interesting than a cofactor derivative. Moreover, several compounds have been designed with an arginine or an arginine analog to enhance their activities [49], and disruption of protein dimers by using small molecules has also been reported [50,51]. Table 1 shows four conserved arginines (Arg 102, Arg 350, Arg 433 and Arg 506) which are important for the catalytic activity of rat Transketolase, as demonstrated by site-directed mutagenesis (arginine to alanine mutation) [14], and their equivalent residues in yeast and human variants.…”

Section: Description Of Dimerization Sites Involving Arginine Residuesmentioning

confidence: 99%

Homology modeling of human Transketolase: Description of critical sites useful for drug design and study of the cofactor binding mode

Obiol-Pardo

Rubio-Martínez

2009

Journal of Molecular Graphics and Modelling

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Thyroxine-derivatives of lipopeptides: bifunctional dimerization inhibitors of human immunodeficiency virus-1 protease

Cited by 24 publications

References 28 publications

Analysis and characterization of dimerization inhibition of a multi-drug-resistant Human Immunodeficiency Virus Type 1 protease using a novel size-exclusion chromatographic approach

Analysis and characterization of dimerization inhibition of a multi-drug-resistant Human Immunodeficiency Virus Type 1 protease using a novel size-exclusion chromatographic approach

Current and Novel Inhibitors of HIV Protease

Homology modeling of human Transketolase: Description of critical sites useful for drug design and study of the cofactor binding mode

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