Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase.

ABSTRACT: Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in sil

SUBMITTER: Sakamoto Y 

PROVIDER: S-EPMC6753110 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature