Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

The cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S constitutes the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low molecular weight inhibitors for cathepsin F have not been developed so far. An active site mapping with 52 dipeptide nitriles, reacting as covalent-reversible inhibitors, was performed to draw structureactivity relationships for the non-primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N-(4-phenylbenzoyl)-leucyl-glycine nitrile) and 12 (N-(4-phenylbenzoyl)-leucyl-methionine nitrile) were potent inhibitors of human cathepsin F with Ki values less than 10 nM. With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure-activity relationships for this
series of cathepsin F inhibitors.