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 centers. Here, we describe the design and execution of an approach to this broad problem by merging principles associated 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” – COPAs) that 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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“…For the rapid and efficient selection of best compounds among a library of α-helix mimetics, we developed a convenient HTS method by taking advantage of a bead-based screening platform, which was originally developed by Lam and colleagues for screening peptides (42) and has been successfully applied to cyclic peptides and peptidomimetics such as β-peptides and peptoids (29,(43)(44)(45)(46)(47). Relative to conventional HTS assays, on-bead screening has several advantages (48).…”

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“…For example, my laboratory has elaborated the classical “sub-monomer” synthesis of peptoids (Zuckermann, 1992) (oligomers of N-substituted glycines) to facilitate the synthesis of peptoid-inspired compounds with more chemically complex and conformationally restricted main chain scaffolds (Fig. 2) (Aditya and Kodadek, 2012; Aquino et al, 2011; Gao and Kodadek, 2013; Sarma and Kodadek, 2011; Suwal and Kodadek, 2013). Very recently, we screened one such library (Fig.…”

“…2) against several soluble IgG forms of CLL BCRs(Sarkar et al, 2014). This library was largely built using a COPA (chiral oligomers of pentenoic amides) scaffold, developed by Micalizio and co-workers (Aquino et al, 2011). Because of strong allylic 1,3 strain interactions, the COPA units greatly stiffen the main chain of the molecule relative to peptides or peptoids.…”

“…Because of strong allylic 1,3 strain interactions, the COPA units greatly stiffen the main chain of the molecule relative to peptides or peptoids. Thus even small COPA oligomers fold into stable structures determined by the absolute stereochemistry at the chiral center (Aquino et al, 2011). About 1.3 million beads displaying diverse tetramers were screened by first incubating the OBOC library with a mixture of antibodies from patients that did not suffer from CLL.…”

“…Another important advance has been the development of new classes of oligomers that are far more conformationally constrained than the floppy peptoids (Aditya and Kodadek, 2012; Aquino et al, 2011; Gao and Kodadek, 2013; Sarma and Kodadek, 2011; Suwal and Kodadek, 2013) (Fig. 2A).…”