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A biomimetic polyketide-inspired approach to small-molecule ligand discovery

Abstract

The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on ‘natural product-like’ libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed ‘chiral oligomers of pentenoic amides’, COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.

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Figure 1: Natural and synthetic oligomers, polyketide-derived natural products and a polyketide-inspired class of chiral and conformationally rigid synthetic oligomers.
Figure 2: Stereochemistry of the COPA backbone is anticipated to have a substantial impact on skeletal shape and the disposition of side chains in space.
Figure 3: Chemical development of COPA oligomers from a general oligomerization strategy, asymmetric synthesis and library construction.
Figure 4: COPA library synthesis, screening, structure elucidation and validation.

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References

  1. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Tan, D. S. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nature Chem. Biol. 1, 74–84 (2005).

    Article  CAS  Google Scholar 

  3. Spiegel, D. A., Schroeder, F. C., Duvall, J. R. & Schreiber, S. L. An oligomer-based approach to skeletal diversity in small-molecule synthesis. J. Am. Chem. Soc. 128, 14766–14767 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Nielsen, T. E. & Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56 (2008).

    Article  CAS  Google Scholar 

  5. Houghten, R. A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen–antibody interaction at the level of individual amino acids. Proc. Natl Acad. Sci. USA 82, 5131–5135 (1985).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Thompson, L. A. & Ellman, J. A. Synthesis and applications of small molecule libraries. Chem. Rev. 96, 555–600 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Khosla, C., Kapur, S. & Cane, D. E. Revisiting the modularity of modular polyketide synthases. Curr. Opin. Chem. Biol. 13, 135–143 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Walsh, C. T. The chemical versatility of natural-product assembly lines. Acc. Chem. Res. 41, 4–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Nielsen, P. E. Peptide nucleic acids (PNA) in chemical biology and drug discovery. Chem. Biodivers. 7, 786–804 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Seebach, D. & Gardiner, J. β-Peptidic peptidomimetics. Acc. Chem. Res. 41, 1366–1375 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Gellman, S. H. Foldamers: a manifesto. Acc. Chem. Res. 31, 173–180 (1998).

    Article  CAS  Google Scholar 

  12. Horne, W. S. & Gellman, S. H. Foldamers with heterogeneous backbones. Acc. Chem. Res. 41, 1399–1408 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Nowick, J. S. Exploring β-sheet structure and interactions with chemical model systems. Acc. Chem. Res. 41, 1319–1330 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Robinson, J. A. β-Hairpin peptidomimetics: design, structures and biological activities. Acc. Chem. Res. 41, 1278–1288 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Schafmeister, C. E., Brown, Z. Z. & Gupta, S. Shape-programmable macromolecules. Acc. Chem. Res. 41, 1387–1398 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Li, X., Wu, T.-D. & Yang, D. α-Aminoxy acids: new possibilities from foldamers to anion receptors and channels. Acc. Chem. Res. 41, 1428–1438 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Summerton, J. Morpholino antisense oligomers: the case for an RNase H-independent structural type. Biochim. Biophys. Acta. 1489, 141–158 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Dervan, P. B. Molecular recognition of DNA by small molecules. Bioorg. Med. Chem. 9, 2215–2235 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Wuereb, H., Maletic, M., Gildersleeve, J., Pelczer, I. & Kahne, D. Design of an oligosaccharide scaffold that binds in the minor groove of DNA. J. Am. Chem. Soc. 122, 1883–1890 (2000).

    Article  Google Scholar 

  20. Davis, J. M., Tsou, L. K. & Hamilton, A. D. Synthetic non-peptide mimetics of α-helices. Chem. Soc. Rev. 36, 326–334 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Kumar, K. & Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 48, 3224–3242 (2009).

    Article  CAS  Google Scholar 

  22. Hoffmann, R. W. Flexible molecules with defined shape—conformational design. Angew. Chem. Int. Ed. 31, 1124–1134 (1992).

    Article  Google Scholar 

  23. Simon, R. J. et al. Peptoids: a modular approach to drug discovery. Proc. Natl Acad. Sci. USA 89, 9367–9371 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Zuckermann, R. N., Kerr, J. M., Kent, S. B. H. & Moos, W. H. Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 114, 10646–10647 (1992).

    Article  CAS  Google Scholar 

  25. Zuckermann, R. N. & Kodadek, T. Peptoids as potential therapeutics. Curr. Opin. Mol. Ther. 11, 299–307 (2009).

    CAS  PubMed  Google Scholar 

  26. Wilson, D. S., Keefe, A. D. & Szostak, J. W. The use of mRNA display to select high-affinity protein-binding peptides. Proc. Natl Acad. Sci. USA 98, 3750–3755 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Czarnik, A. W. Encoding strategies in combinatorial chemistry. Proc. Natl Acad. Sci. USA 94, 12738–12739 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Ho, G.-J. & Mathre, D. J. Lithium-initiated imide formation. A simple method for N-acylation of 2-oxazolidinones and bornane-2,10-sultam. J. Org. Chem. 60, 2271–2273 (1995).

    Article  CAS  Google Scholar 

  29. Evans, D. A., Tedrow, J. S., Shaw, J. T. & Downey, C. W. Diastereoselective magnesium halide-catalyzed anti-aldol reactions of chiral N-acyloxazolidinones. J. Am. Chem. Soc. 124, 392–393 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Ravikumar, P. C., Yao, L. & Fleming, F. F. Allylic and allenic halide synthesis via NbCl5- and NbBr5-mediated alkoxide rearrangements. J. Org. Chem. 74, 7294–7299 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Xiao, X., Yu, P., Lim, H-S., Sikder, D. & Kodadek, T. Design and synthesis of a cell-permeable synthetic transcription factor mimic. J. Comb. Chem. 9, 592–600 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Levine, A. J. & Oren, M. The first 30 years of p53: growing ever more complex. Nature Rev. Cancer 9, 749–758 (2009).

    Article  CAS  Google Scholar 

  33. Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R. & Lane, D. P. Awakening guardian angels: drugging the p53 pathway. Nature Rev. Cancer 9, 862–873 (2009).

    Article  CAS  Google Scholar 

  34. Cochran, A. G. Antagonists of protein–protein interactions. Chem. Biol. 7, R85–R94 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Syka, J. E. P., Coon, J. J., Schroeder, M. J., Shabanowitz, J. & Hunt, D. F. Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry. Proc. Natl Acad. Sci. USA 101, 9528–9533 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Lambert, J. M. et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376–388 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Boekler, F. M. et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl Acad. Sci. USA 105, 10360–10365 (2008).

    Article  Google Scholar 

  38. Coombs, T. C., Lushington, G. H., Douglas, J. & Aubé, J. 1,3-Allylic strain as a strategic diversification element for constructing libraries of substituted 2-arylpiperidines. Angew. Chem. Int. Ed. 50, 2734–2737 (2011).

    Article  CAS  Google Scholar 

  39. Clemons, P. A. et al. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Morton, D., Leach, S., Cordier, C., Warriner, S. & Nelson, A. Synthesis of natural-product-like molecules with over eighty distinct scaffolds. Angew. Chem. Int. Ed. 48, 104–109 (2009).

    Article  CAS  Google Scholar 

  41. Luo, T. & Schreiber, S. L. Gold(I)-catalyzed coupling reactions for the synthesis of diverse small molecules using the build/couple/pair strategy. J. Am. Chem. Soc. 131, 5667–5674 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Uchida, T., Rodriguez, M. & Schreiber, S. L. Skeletally diverse small molecules using a build/couple/pair strategy. Org. Lett. 11, 1559–1562 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Reddy, M. M. et al. Identification of candidate IgG biomarkers for Alzheimer's Disease via combinatorial library screening. Cell 144, 132–142 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Udugamasooriya, D. G., Dineen, S. P., Brekken, R. A. & Kodadek, T. A peptoid ‘antibody surrogate’ that antagonizes VEGF receptor 2 activity. J. Am. Chem. Soc. 130, 5744–5752 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

G.C.M. acknowledges financial support from the Fidelity Biosciences Research Initiative, the Scripps Research Institute, Scripps Florida. T.K. acknowledges support from the NHLBI (N01-HV-00242).

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Authors

Contributions

G.C.M. and T.K. conceived and directed the project. C.A. and M.S. contributed equally to the execution of this work. C.A. prepared acid 1 and conducted all solution-phase chemistry. M.S. and C.A. conducted all solid-phase experiments, library synthesis, decoding experiments and biochemical evaluation of the hits. M.S. purified the p53–DBD, which was cloned and expressed by K.M., and conducted the biochemical characterization of the hit. M.C. developed the ETD-based method for compound decoding. G.C.M. and T.K. wrote the manuscript.

Corresponding authors

Correspondence to Thomas Kodadek or Glenn C. Micalizio.

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Aquino, C., Sarkar, M., Chalmers, M. et al. A biomimetic polyketide-inspired approach to small-molecule ligand discovery. Nature Chem 4, 99–104 (2012). https://doi.org/10.1038/nchem.1200

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