Abstract
Protein--protein interactions (PPIs) play a central role in virtually all biological processes and have been the focus of intense investigation from structural molecular biology to cell biology for the majority of the last two decades and, more recently, are emerging as important targets for pharmaceutical intervention. A common motif found at the interface of PPIs is the α-helix, suggesting that, in the same way as the "lock and key" model has evolved for competitive inhibition of enzymes, it should be possible to elaborate "rule-based" approaches for inhibition of helix-mediated PPIs. This review will describe the biological function and structural features of a series of representative helix-mediated PPIs and discuss approaches that are being developed to target these interactions with small molecules that employ non-natural amino acids.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Amino Acids / chemistry
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Capsid / metabolism
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Cell Cycle Proteins
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HIV Envelope Protein gp41 / chemistry
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HIV Envelope Protein gp41 / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Peptides / chemistry*
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Peptides / pharmacology*
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Peptidomimetics
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Protein Interaction Domains and Motifs / drug effects*
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Protein Interaction Mapping
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Notch / chemistry
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Receptors, Notch / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / metabolism
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / metabolism
Substances
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Amino Acids
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Cell Cycle Proteins
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HIF1A protein, human
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HIV Envelope Protein gp41
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Hypoxia-Inducible Factor 1, alpha Subunit
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MDM4 protein, human
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Nuclear Proteins
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Peptides
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Peptidomimetics
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RE1-silencing transcription factor
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Receptors, Cytoplasmic and Nuclear
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Receptors, Notch
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Repressor Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2