Inverse pharmacology: Approaches and tools for introducing druggability into engineered proteins

A major feature of twenty-first century medical research is the development of therapeutic strategies that use ‘biologics’ (large molecules, usually engineered proteins) and living cells instead of, or as well as, the small molecules that were the basis of pharmacology in earlier eras. The high power of these techniques can bring correspondingly high risk, and therefore the need for the potential for external control. One way of exerting control on therapeutic proteins is to make them responsive to small molecules; in a clinical context, these small molecules themselves have to be safe. Conventional pharmacology has resulted in thousands of small molecules licensed for use in humans, and detailed structural data on their binding to their protein targets. In principle, these data can be used to facilitate the engineering of drug-responsive modules, taken from natural proteins, into synthetic proteins. This has been done for some years (for example, Cre-ERT2) but usually in a painstaking manner. Recently, we have developed the bioinformatic tool SynPharm to facilitate the design of drug-responsive proteins. In this review, we outline the history of the field, the design and use of the Synpharm tool, and describe our own experiences in engineering druggability into the Cpf1 effector of CRISPR gene editing.