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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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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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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The authors declare no competing financial interests.

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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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