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Aromatic and heteroaromatic amines (ArNH(2)) represent a class of potential mutagens that after being metabolically activated covalently modify DNA. Activation of ArNH(2) in many cases starts with N-hydroxylation by P450 enzymes, primarily CYP1A2. Poor understanding of structure-mutagenicity relationships of ArNH(2) limits their use in drug discovery(More)
The metabolism of aromatic and heteroaromatic amines (ArNH₂) results in nitrenium ions (ArNH⁺) that modify nucleobases of DNA, primarily deoxyguanosine (dG), by forming dG-C8 adducts. The activated amine nitrogen in ArNH⁺ reacts with the C8 of dG, which gives rise to mutations in DNA. For the most mutagenic ArNH₂, including the majority of known genotoxic(More)
Primary aromatic and heteroaromatic amines are notoriously known as potential mutagens and carcinogens. The major event of the mechanism of their mutagenicity is N-hydroxylation by P450 enzymes, primarily P450 1A2 (CYP1A2), which leads to the formation of nitrenium ions that covalently modify nucleobases of DNA. Energy profiles of the NH bond activation(More)
Due to its implication in pathologies of prevalent diseases such as chronic obstructive pulmonary disease, fibrosis, bronchiectasis and ARDS, the serine protease, human neutrophil elastase, has been in focus for drug-development efforts over the last two decades. In recent years, continued efforts to identify and optimize novel mechanism-based inhibitors(More)
A class of inhibitors of mitogen activated protein kinase-activated kinase 2 (MK2) was discovered via high-throughput screening. This compound class demonstrates activity against the enzyme with sub-microM IC(50) values, and suppresses LPS-induced TNFalpha levels in THP-1 cells. MK2 inhibition kinetic measurements indicated mixed binding approaching non-ATP(More)
In the last 2 decades, renewed attention to neglected tropical diseases (NTDs) has spurred the development of antiparasitic agents, especially in light of emerging drug resistance. The need for new drugs has required in vitro screening methods using parasite culture. Furthermore, clinical laboratories sought to correlate in vitro susceptibility methods with(More)
Macrocyclic peptides have promising therapeutic potential but the scaling up of their chemical synthesis is challenging. The cyanobactin macrocyclase PatGmac is an efficient tool for production but is limited to substrates containing 6-11 amino acids and at least one thiazoline or proline. Here we report a new cyanobactin macrocyclase that can cyclize(More)
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