Small-Molecule Dimerization Inhibitors of Wild-Type and Mutant HIV Protease:  A Focused Library Approach

Shultz, Michael D.; Ham, Young-Wan; Lee, Song-Gil; Davis, David A.; Brown, C.K.; Chmielewski, Jean

doi:10.1021/ja048139n

Cited by 44 publications

(40 citation statements)

References 14 publications

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“…A few groups have reported PR dimerization inhibitors targeting the terminal interface of PR (9)(10)(11)(12). However, none of such inhibitors have been of clinical utility, probably because PR dimers, once formed, are highly stable to "de-dimerize" with the potent dimerization forces in the termini interface (13).…”

Section: D25nmentioning

confidence: 99%

Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir

Hayashi

Takamune

Nirasawa³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Dimerization of HIV-1 protease (PR) plays a critical role in the replication of HIV-1. Darunavir (DRV) inhibits not only proteolytic activity but also PR dimerization. The present study shows that PR dimerization process undergoes two steps and that DRV inhibits the first step of PR dimerization by binding to PR monomers in a one-to-one molar ratio. The present study also demonstrates that DRV binds to a transframe precursor PR protein, indicating that DRV’s monomer binding is involved in the Gag-Pol autoprocessing inhibition. To our knowledge, the present report represents the first demonstration of the two-step PR dimerization dynamics and the mechanism of dimerization inhibition by DRV, which should help design further, more potent novel PR inhibitors.

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Section: D25nmentioning

confidence: 99%

Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir

Hayashi

Takamune

Nirasawa³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Unlike all other crystal structures of the free protease, this 'monomeric' protease exhibits the closed flap conformation. Last but not least, there has been a continuing effort to design inhibitors of protease dimerization [54,55]. An interesting recent report [56] demonstrated that some of the inhibitors initially designed to prevent dimerization actually did not disrupt the dimer interface and yet showed substantial protease inhibition.…”

Section: Drug Design Targeting Protein Flexibility -New Allosteric Inmentioning

confidence: 99%

Targeting structural flexibility in HIV-1 protease inhibitor binding

Horn̆ák

Simmerling

2007

Drug Discovery Today

108

104

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SummaryHIV-1 protease remains an important AIDS drug target. Even though it has been known that ligand binding induces large conformational changes in the protease, the dynamic aspects of binding have been largely ignored. Several computational models describing protease dynamics have been reported recently. These have reproduced experimental observations, and also explained how ligands gain access to the binding site through dynamic behavior of the protease. Specifically, the transitions between three different conformations of the protein have been modeled in atomic detail. Two of these forms were determined by crystallography, the third one was implied by NMR experiments. Based on these computational models, it has been suggested that binding of inhibitors in allosteric sites may affect protease flexibility and disrupt its function.

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“…The most potent hit, PPBH3-1, bound Bcl-2 with a K d value of 52 ± 5 nM, corresponding to a 100-fold stronger binding affinity in comparison to Bak 72-87 [11]. The authors attributed this enhanced affinity to the rigid, pre-organization of the normally unstructured Bak [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] binding epitope conferred by the -helix of aPP. Further studies probed the structural requirements for selective binding between the designed peptide motifs and two anti-apoptotic protein analogs, Bcl-2 and Bcl-x L [12].…”

Section: Miniature Protein Motifsmentioning

confidence: 99%

“…Focused libraries containing single and double mutations generated several potent small-molecule dimerization inhibitors of HIV-1 protease with the best inhibitor, 27, displaying a K i value of 29 nM (Fig. 13) [81][82][83].…”

Section: Crosslinked -Strand Mimetic Scaffoldsmentioning

confidence: 99%

Scaffolds for Blocking Protein-Protein Interactions

Hershberger¹,

Lee²,

Chmielewski

2007

CTMC

Self Cite

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Due to the pivotal roles that protein-protein interactions play in a plethora of biological processes, the design of therapeutic agents targeting these interactions has become an attractive and important area of research. The development of such agents is faced with a variety of challenges. Nevertheless, considerable progress has been made in the design of proteomimetics capable of disrupting protein-protein interactions. Those inhibitors based on molecular scaffold designs hold considerable interest because of the ease of variation in regard to their displayed functionality. In particular, protein surface mimetics, alpha-helical mimetics, beta-sheet/beta-strand mimetics, as well as beta-turn mimetics have successfully modulated protein-protein interactions involved in such diseases as cancer and HIV. In this review, current progress in the development of molecular scaffolds designed for the disruption of protein-protein interactions will be discussed with an emphasis on those active against biological targets.

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Small-Molecule Dimerization Inhibitors of Wild-Type and Mutant HIV Protease: A Focused Library Approach

Cited by 44 publications

References 14 publications

Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir

Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir

Targeting structural flexibility in HIV-1 protease inhibitor binding

Scaffolds for Blocking Protein-Protein Interactions

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