6960-34-5Relevant articles and documents
Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template
Gall, Flavio M.,Hohl, Deborah,Frasson, David,Wermelinger, Tobias,Mittl, Peer R. E.,Sievers, Martin,Riedl, Rainer
supporting information, p. 4051 - 4055 (2019/02/16)
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nm) and MMP-9 (IC50: 140 nm).
Asymmetric Transamination of α-Keto Acids Catalyzed by Chiral Pyridoxamines
Lan, Xiaoyu,Tao, Chuangan,Liu, Xuliang,Zhang, Aina,Zhao, Baoguo
supporting information, p. 3658 - 3661 (2016/08/16)
A new type of novel chiral pyridoxamines 3a-g containing a side chain has been developed. The pyridoxamines displayed catalytic activity and promising enantioselectivity in biomimetic asymmetric transamination of α-keto acids, to give various α-amino acids in 47-90% yields with up to 87% ee's under very mild conditions. An interesting effect of the side chain on enantioselectivity was observed in the reaction.
Enzymatic conversion of unnatural amino acids by yeast D-amino acid oxidase
Caligiuri, Antonio,D'Arrigo, Paola,Rosini, Elena,Tessaro, Davide,Molla, Gianluca,Servi, Stefano,Pollegioni, Loredano
, p. 2183 - 2190 (2007/10/03)
Unnatural amino acids, particularly synthetic α-amino acids, are becoming crucial tools for modern drug discovery research. In particular, this application requires enantiomerically pure isomers. In this work we report on the resolution of racemic mixtures of the amino acids D,L-naphthylalanine and D,L-naphthylglycine by using a natural enzyme, D-amino acid oxidase from the yeast Rhodotorula gracilis. A significant improvement of the bioconversion is obtained using a single-point mutant enzyme designed by a rational approach. With this D-amino acid oxidase variant the complete resolution of all the unnatural amino acids tested was obtained: in this case, the bioconversion requires a shorter time and a lower amount of biocatalyst compared to the wild-type enzyme. The simultaneous production of the corresponding α-keto acid, a possible precursor of the amino acid in the L-form, improves the significance of the procedure.