Biosynthetic Incorporation of Non-native Aryl Acid Building Blocks into Peptide Products Using Engineered Adenylation Domains.

Nonribosomal peptides (NRPs), one of the most widespread secondary metabolites in nature, with therapeutically significant activities, are biosynthesized by modular nonribosomal peptide synthetases (NRPSs). Aryl acids contribute to the structural diversity of NRPs as well as nonproteinogenic amino acids and keto acids. We previously confirmed that a single Asn-to-Gly substitution in the 2,3-dihydroxybenzoic acid-activating adenylation (A) domain EntE involved in enterobactin biosynthesis accepts monosubstituted benzoic acid derivatives with nitro, cyano, bromo, and iodo functionalities at the 2 or 3 positions.

Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice.

There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and C for drug candidates identified as a "victims" of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the AUC ratio (AUCR) of a few CYP3A substrates in the presence and absence of CYP3A inducers. In the present study, we investigate the predictability of AUCR and also C ratio (CR) in additional 54 clinical studies.

Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag.

Inverse kinetic isotope effect of ammonia decomposition over Ru/CeO using deuterated ammonia.

This study investigated the ammonia decomposition mechanism over Ru/CeO. Isotopic tests using ND revealed that the rate-determining step involves adsorbed nitrogen atoms on Ru. Moreover, an inverse kinetic isotope effect where ND decomposition was faster than NH was clearly observed.