Identification of small-molecule modulators of protein–protein interactions (PPIs) is recognized as a challenging objective. This stems in part from the fact that the surfaces of proteins involved at PPI interfaces are larger than historical small-molecule drug targets, are topographically diverse, and possess recognition domains that are spatially divorced from one another. These molecular recognition features coupled with the fact that hit rates from high-throughput screening (HTS) libraries against PPIs are much lower than against other targets – which is perhaps unsurprising given HTS libraries are biased towards known targets and synthetic methodologies – have led to a perception that PPIs are ‘undruggable’ or, more accurately, ‘unligandable’ [1,2]. This view has successfully been challenged by the discovery of the Nutlins using HTS, while fragment-based drug discovery has emerged as a target ‘agnostic’ approach amenable to PPIs, exemplified by the discovery of ABT-737 and subsequent iterations [3]. Despite these successes, the ability to design chemical leads or at least learn how to assemble better libraries with molecular features more suited to PPIs is appealing. Peptidomimetics (compounds containing nonpeptidic structural elements that are capable of mimicking or antagonizing the biological actions of their natural parent peptide) would seem to represent a desirable starting point. More specifically, secondary structural elements (e.g., α-helices and β-sheets) and β-turns have been found at a number of PPI interfaces [2]; in turn, using small molecules to reproduce the vectoral presentation of recognition functionality found on secondary motifs represents a viable strategy for intervention. Where designed molecules achieve this level of mimicry they might be described more suitably as proteomimetics (i.e., compounds mimicking a segment of protein). The current chapter will introduce some of the early examples of proteomimetic compounds and illustrate how these designs are now being taken forward to generate second-generation scaffolds for which library syntheses are possible.
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