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Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors
1, 2 , 1, 3 , 1 , 2 , 3 , * 1
1  University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany
2  Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany
3  Department of Life Science Informatics, B-IT, Dahlmannstr. 2, 53113 Bonn, Germany

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

Cysteine cathepsins are lysosomal cysteine proteases which play roles in many physiological processes. Cathepsin F is predominantly expressed in macrophages. Major histocompatibility complex class II molecules (MHC-II) are expressed by antigen-presenting cell types including macrophages, B cells, and dendritic cells. The cleavage of the invariant chain is the key event in the pathway of MHC-II complexes. Cathepsin S was described as the major processing enzyme of the invariant chain, but it was shown that cathepsin F can adopt its role in cathepsin S deficient mice.[1] Low molecular weight inhibitors for cathepsin F have not been investigated so far. We have chosen the dipeptide nitrile[2] chemotype to develop covalent-reversible inhibitors for this target.

An active site mapping with a library of 52 nitrile-based cathepsin inhibitors was performed at human cathepsin F to draw structure-activity relationships. With the kinetic data in hand, new compounds with optimized residues in P1, P2 and P3 position were synthesized and evaluated. With all dipeptide nitriles including the newly synthesized derivatives, a 3D activity landscape was generated to visualize similarity-activity relationships of this series of cathepsin F inhibitors.



[1] Shi GP, Bryant RA, Riese R, Verhelst S, Driessen C, Li Z, Brömme D, Ploegh HL, Chapman HA. J. Exp. Med. 2000, 191, 1177-1186.

[2] Frizler M, Stirnberg M, Sisay MT, Gütschow M. Curr. Top. Med. Chem. 2010, 10, 294-322.

Keywords: 3D activity landscapes · cysteine proteases · human cathepsins · nitrile inhibitors