High Temperature Requirement A (HTRA) proteins are serine proteases of the S1 family (trypsin/chymotrypsin-like). HTRA1 is supposed to play a role in macular degeneration, and HTRA2 has been associated with cell death in reperfusion-ischemia. Therefore, HTRA proteins might represent novel therapeutic targets. However, currently no inhibitors with drug-like characteristics and thus promising potential for pharmaceutical development are available. Researchers of the University of Duisburg-Essen have now demonstrated that Ahp-cyclodepsipeptides represent a suitable scaffold for generating target-tailored inhibitors of serine proteases. They have developed a practical mixed solid- and solution-phase synthesis that allows the customized synthesis of Ahp-cyclodepsipeptides and thus tailored inhibitor synthesis. The applicability of this approach was shown by the generation of the most potent human HTRA1 as well as HTRA2 protease inhibitors to date (see figure). Inhibitory potency of the synthesized substances was proven in binding studies and cell-based assays.