Evaluation of bisbenzamidines as inhibitors for matriptase-2

Improving binding entropy by higher ligand symmetry? – A case study with human matriptase

“…As known for several trypsin-like proteases, benzamidine moieties were successfully used to address the S1 subsite as arginine mimetics. 22,23 Exemplarily, this can be observed in the MT-SP1–ligand complex structure of the tri-basic inhibitor ( N -(4-aminocyclohexyl)-3,5-bis(4-carbamimidoylphenoxy)benzamide, 15 ) (Fig. 1, S1B, RCSB protein data bank (PDB) ID: ).…”

A Short Peptide Inhibitor as an Activity-Based Probe for Matriptase-2

“…Since MT-2 prefers substrates with arginine at P1, P2 or P3 and P4 positions [ 9 , 15 , 16 , 17 ], this knowledge can and has been used to design small peptide inhibitors and peptidomimetic activity-based probes. Already described low-molecular weight MT-2 inhibitors include, for example, amidinophenylalanine derivatives [ 18 ], peptidic ketones [ 19 , 20 ], sunflower trypsin inhibitor-1 (SFTI-1) analogues [ 21 ], and bisbenzamidines [ 22 , 23 , 24 ], the latter type of compounds also being established as fungicides and antiprotozoal agents [ 25 , 26 , 27 ] and able to bind to the double strand DNA [ 28 , 29 ]. Here we present a short biotinylated peptide probe with a chloromethyl ketone warhead (biotin-RQRR-CMK) as an irreversible inhibitor and activity-based probe for MT-2 ( Figure 1 ).…”

“…This probe was originally developed for the related enzyme matriptase [ 30 , 31 ], which exhibits a similar substrate specificity [ 32 ]. Selectivity for MT-2 over matriptase has rarely been observed within series of synthetic inhibitors [ 9 , 18 , 23 , 24 ], but has been achieved with certain SFTI-1 analogues [ 21 ] and, in particular, peptidic ketones containing unnatural amino acids, such as l - allo -threonine at P2 position [ 20 ]. Its side chain may favorably interact with 99 His of the S2 pocket of MT-2, while matriptase has Phe at this position [ 19 , 20 , 33 ].…”