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.
Subscribe to Journal
Get full journal access for 1 year
only $14.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).
Tan, D. S. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nature Chem. Biol. 1, 74–84 (2005).
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).
Nielsen, T. E. & Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56 (2008).
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).
Thompson, L. A. & Ellman, J. A. Synthesis and applications of small molecule libraries. Chem. Rev. 96, 555–600 (1996).
Khosla, C., Kapur, S. & Cane, D. E. Revisiting the modularity of modular polyketide synthases. Curr. Opin. Chem. Biol. 13, 135–143 (2009).
Walsh, C. T. The chemical versatility of natural-product assembly lines. Acc. Chem. Res. 41, 4–10 (2008).
Nielsen, P. E. Peptide nucleic acids (PNA) in chemical biology and drug discovery. Chem. Biodivers. 7, 786–804 (2010).
Seebach, D. & Gardiner, J. β-Peptidic peptidomimetics. Acc. Chem. Res. 41, 1366–1375 (2008).
Gellman, S. H. Foldamers: a manifesto. Acc. Chem. Res. 31, 173–180 (1998).
Horne, W. S. & Gellman, S. H. Foldamers with heterogeneous backbones. Acc. Chem. Res. 41, 1399–1408 (2008).
Nowick, J. S. Exploring β-sheet structure and interactions with chemical model systems. Acc. Chem. Res. 41, 1319–1330 (2008).
Robinson, J. A. β-Hairpin peptidomimetics: design, structures and biological activities. Acc. Chem. Res. 41, 1278–1288 (2008).
Schafmeister, C. E., Brown, Z. Z. & Gupta, S. Shape-programmable macromolecules. Acc. Chem. Res. 41, 1387–1398 (2008).
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).
Summerton, J. Morpholino antisense oligomers: the case for an RNase H-independent structural type. Biochim. Biophys. Acta. 1489, 141–158 (1999).
Dervan, P. B. Molecular recognition of DNA by small molecules. Bioorg. Med. Chem. 9, 2215–2235 (2001).
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).
Davis, J. M., Tsou, L. K. & Hamilton, A. D. Synthetic non-peptide mimetics of α-helices. Chem. Soc. Rev. 36, 326–334 (2007).
Kumar, K. & Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 48, 3224–3242 (2009).
Hoffmann, R. W. Flexible molecules with defined shape—conformational design. Angew. Chem. Int. Ed. 31, 1124–1134 (1992).
Simon, R. J. et al. Peptoids: a modular approach to drug discovery. Proc. Natl Acad. Sci. USA 89, 9367–9371 (1992).
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).
Zuckermann, R. N. & Kodadek, T. Peptoids as potential therapeutics. Curr. Opin. Mol. Ther. 11, 299–307 (2009).
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).
Czarnik, A. W. Encoding strategies in combinatorial chemistry. Proc. Natl Acad. Sci. USA 94, 12738–12739 (1997).
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).
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).
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).
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).
Levine, A. J. & Oren, M. The first 30 years of p53: growing ever more complex. Nature Rev. Cancer 9, 749–758 (2009).
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).
Cochran, A. G. Antagonists of protein–protein interactions. Chem. Biol. 7, R85–R94 (2000).
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).
Lambert, J. M. et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376–388 (2009).
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).
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).
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).
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).
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).
Uchida, T., Rodriguez, M. & Schreiber, S. L. Skeletally diverse small molecules using a build/couple/pair strategy. Org. Lett. 11, 1559–1562 (2009).
Reddy, M. M. et al. Identification of candidate IgG biomarkers for Alzheimer's Disease via combinatorial library screening. Cell 144, 132–142 (2011).
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).
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).
The authors declare no competing financial interests.
About this article
Cite this article
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
Peptoids with Substituents on the Backbone Carbons as Conformationally Constrained Synthetic Oligoamides
Journal of Synthetic Organic Chemistry, Japan (2020)
Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers
The Journal of Organic Chemistry (2020)
Remarkable Potential of Zerumbone to Generate a Library with Six Natural Product-like Skeletons by Natural Material-Related Diversity-Oriented Synthesis
The Journal of Organic Chemistry (2020)
Re-Engineering of Yohimbine’s Biological Activity through Ring Distortion: Identification and Structure–Activity Relationships of a New Class of Antiplasmodial Agents
ACS Infectious Diseases (2020)
Structural characterization of a peptoid-inspired conformationally constrained oligomer (PICCO) bound to streptavidin
Chemical Communications (2020)