Small-Molecule Inhibitors of HIV-1 Protease Dimerization Derived from Cross-Linked Interfacial Peptides

Shultz, Michael D.; Bowman, Michael J.; Ham, Young-Wan; Zhao, Xuimin; Tora, George; Chmielewski, Jean

doi:10.1002/1521-3757(20000804)112:15<2822::aid-ange2822>3.0.co;2-1

Cited by 13 publications

(4 citation statements)

References 28 publications

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“…In the Zhang-Poorman analysis, a dimerization inhibitor alters the y-intercept value by a factor of [I]/K i , but has no effect on the slope [20,27]. Dimerization inhibitors are easily identified using the Zhang-Poorman plot as they provide lines that are parallel with that from the protease alone, while competitive and non-competitive inhibitors give non-parallel lines [36]. Zhang-Poorman plot has been successfully applied in many protease dimerization inhibitor studies [20,23,25,27,36].…”

Section: Key Residue Analysis Of the N-finger Of Sars 3cl Proteinasementioning

confidence: 99%

The N-terminal octapeptide acts as a dimerization inhibitor of SARS coronavirus 3C-like proteinase

Wei

Fan

Chen

et al. 2006

Biochemical and Biophysical Research Communications

116

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The 3C-like proteinase of severe acute respiratory syndrome (SARS) coronavirus has been proposed to be a key target for structural-based drug design against SARS. Accurate determination of the dimer dissociation constant and the role of the N-finger (residues 1-7) will provide more insights into the enzyme catalytic mechanism of SARS 3CL proteinase. The dimer dissociation constant of the wild-type protein was determined to be 14.0microM by analytical ultracentrifugation method. The N-finger fragment of the enzyme plays an important role in enzyme dimerization as shown in the crystal structure. Key residues in the N-finger have been studied by site-directed mutagenesis, enzyme assay, and analytical ultracentrifugation. A single mutation of M6A was found to be critical to maintain the dimer structure of the enzyme. The N-terminal octapeptide N8 and its mutants were also synthesized and tested for their potency as dimerization inhibitors. Peptide cleavage assay confirms that peptide N8 is a dimerization inhibitor with a K(i) of 2.20mM. The comparison of the inhibitory activities of N8 and its mutants indicates that the hydrophobic interaction of Met-6 and the electrostatic interaction of Arg-4 contribute most for inhibitor binding. This study describes the first example of inhibitors targeting the dimeric interface of SARS 3CL proteinase, providing a novel strategy for drug design against SARS and other coronaviruses.

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Section: Key Residue Analysis Of the N-finger Of Sars 3cl Proteinasementioning

confidence: 99%

The N-terminal octapeptide acts as a dimerization inhibitor of SARS coronavirus 3C-like proteinase

Wei

Fan

Chen

et al. 2006

Biochemical and Biophysical Research Communications

116

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“…HIV protease is the most studied protein target for IDs (Ast et al, 1998;Bouras et al, 1999;Schramm et al, 1999;Shultz et al, 2000;Chmielewski, 1997, 1999;Ulysse and Chmielewski, 1998;Zutshi et al, 1997Zutshi et al, , 1998. The active dimer of HIV protease is formed by interaction of two b-sheets from each subunit (Wlodawer, Vondrasek, 1998).…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Protein–protein interactions: mechanisms and modification by drugs

Veselovsky

Ivanov

Иванов

et al. 2002

J of Molecular Recognition

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Protein-protein interactions form the proteinaceous network, which plays a central role in numerous processes in the cell. This review highlights the main structures, properties of contact surfaces, and forces involved in protein-protein interactions. The properties of protein contact surfaces depend on their functions. The characteristics of contact surfaces of short-lived protein complexes share some similarities with the active sites of enzymes. The contact surfaces of permanent complexes resemble domain contacts or the protein core. It is reasonable to consider protein-protein complex formation as a continuation of protein folding. The contact surfaces of the protein complexes have unique structure and properties, so they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations have been undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or on the other hand, induce protein dimerization.

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“…The identification of compounds that perturb protein-protein or protein-nucleic acid interactions is extremely challenging, and this is partly due to the lack of effective high-throughput screens. Successes in disrupting protein-protein interactions with small molecules fall into a few classes; surface receptorligand interactions (integrins, IL-1/2, TNF-α [18] ), cytoplasmic targets (iNOS [19] , HIV protease [20] , Bcl-2/xL [21] , XIAP [22] ), and transcription-related targets (MDM2 [23] , LEF-1 [24] , Myc/Max [24] ). Compounds that disrupt protein-nucleic acid interactions are considered to be quite rare.…”

Section: Small Molecule Inhibitor Screeningmentioning

confidence: 99%