期刊
CHEMMEDCHEM
卷 18, 期 6, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200632
关键词
plasmin; trypsin; protease inhibitors; slow-binding inhibition; crystal structures
Two series of macrocyclic plasmin inhibitors with high selectivity were synthesized, and crystal structures of these inhibitors in complex with a Ser195Ala microplasmin mutant were determined. The inhibitors bind to the open active site of plasmin without steric hindrance, explaining their excellent selectivity against other trypsin-like serine proteases. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor led to two analogues with sub-nanomolar inhibition constants.
Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with K-i values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.
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