Beschreibung:
<jats:title>Abstract</jats:title><jats:p>De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand <jats:bold>1</jats:bold> by X‐ray crystallography, which was auto‐tailored by the therapeutic target MMP‐13 through partial self‐degradation and subsequent structure‐based optimization to a highly potent and selective β‐sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non‐proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide <jats:bold>4</jats:bold> (ZHAWOC7726) is membrane permeable with an IC<jats:sub>50</jats:sub> of 21 n<jats:sc>m</jats:sc> for MMP‐13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP‐2 (IC<jats:sub>50</jats:sub>: 170 n<jats:sc>m</jats:sc>) and MMP‐9 (IC<jats:sub>50</jats:sub>: 140 n<jats:sc>m</jats:sc>).</jats:p>