Structure-Guided Rational Design of α/β-Peptide Foldamers with High Affinity for BCL-2 Family Prosurvival Proteins

Authors

  • Prof. Brian J. Smith,

    Corresponding author
    1. Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia)
    • Brian J. Smith, Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia)===

      W. Douglas Fairlie, Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052 (Australia)===

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  • Dr. Erinna F. Lee,

    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052 (Australia)
    2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010 (Australia)
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  • James W. Checco,

    1. Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706 (USA)
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  • Marco Evangelista,

    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052 (Australia)
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  • Prof. Samuel H. Gellman,

    1. Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706 (USA)
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  • Dr. W. Douglas Fairlie

    Corresponding author
    1. Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052 (Australia)
    2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010 (Australia)
    • Brian J. Smith, Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia)===

      W. Douglas Fairlie, Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052 (Australia)===

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Abstract

We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-xL but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-xL was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-xL. Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-xL validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.

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