Natural or engineered peptides serve important biological functions. A general approach to achieve chemical-dependent activation of short peptides will be valuable for spatial and temporal control of cellular processes. Here we present a pair of chemically-activated protein domains (CAPs) for controlling the accessibility of both the N- and C-termini of a peptide. CAPs were developed through directed evolution of an FK506 binding protein (FKBP). By fusing peptides to one or both CAPs, their function is blocked until a small molecule displaces them from the FKBP ligand binding site. We demonstrate that CAPs are generally applicable to a range of short peptides, including a protease cleavage site, the SsrA peptide which dimerizes with the SspB protein, and a nuclear localization signal peptide, with a shield-1 dependent dynamic range up to 156-fold. We also show that the CAPs system can be utilized not only in mammalian cell culture, but also in multiple organs in living animals. Therefore, we have established a novel chemogenetic approach to control peptide activity <i>in vitro</i> and <i>in vivo</i>.

A general method for chemogenetic control of peptide function

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