Supramolecular agents for the binding of challenging protein surface motifs

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All of life is driven by weak and reversible binding events between different biomolecules like proteins and DNA. The contributions of chemists to the study of such systems are often in the form of the creation of a synthetic molecular probe that can bind to a given biomolecule with high potency and selectivity. The most familiar use for such probe molecules is as the precursors to drugs—small organic molecules that block the action of a misbehaving target by potent and selective binding. But chemical probes are actually more often used to open new doors of discovery in the life sciences than they are used as drugs. By binding selectively to a targeted biomolecule within the complex environment of a living cell, chemical probes can allow that target to be labeled, coloured, tracked, or even functionally regulated, in ways that make new discoveries about life processes possible. Chemical probes can also form the basis for molecular “test tube” analysis of biomolecular activities that are useful in the applied areas of disease diagnostics and drug development assays. Almost all of these efforts in the vast area of Chemical Biology rely on the presence of small, concave binding pockets on proteins that are inherently well suited to binding small molecules that have the right size and shape to complement the confined binding pocket. The majority of important biomolecular motifs, however, don’t have concave binding pockets, and because of their relatively flat, featureless topologies their surfaces don’t present a toe-hold that allows small organic molecules to bind to them. Such biomolecules are rarely able to be studied or modulated by chemical approaches. Our proposal is to create a set of chemical probes for these challenging protein surface motifs using large, highly structured, high surface area ‘supermolecules’ or ‘host molecules’ that are defined by having their own rigid, concave binding pockets. This is a reversal of the topology normally encountered for binding events between proteins and chemical probes. We will adapt a battery of modern high-throughput techniques that allow us to make hundreds, thousands, or even billions of such host molecules at a time and to isolate those from among the multitude that have the desired properties. These advances will enable new avenues in life sciences research, and also provide fodder for new assays and other commercial technologies that enable biological and biochemical research.