Patrick Deschamps

Hydroxamic Acids as Potent Inhibitors of Fe(II) and Mn(II) E. Coli Methionine Aminopeptidase: Biological Activities and X-Ray Structures of Oxazole Hydroxamate-Ecmetap-Mn Complexes.

New series of acids and hydroxamic acids linked to five‐membered heterocycles including furan, oxazole, 1,2,4‐ or 1,3,4‐oxadiazole, and imidazole were synthesized and tested as inhibitors against the FeII, CoII, and MnII forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild‐type and acrAB E. coli strains. 2‐Aryloxazol‐4‐ylcarboxylic acids appeared as potent and selective inhibitors of the CoII MetAP form, with IC50 values in the micromolar range, whereas 5‐aryloxazol‐2‐ylcarboxylic acid regioisomers and 5‐aryl‐1,2,4‐oxadiazol‐3‐ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the MnII and FeII forms, with IC50 values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X‐ray crystal structures of EcMetAP‐Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo‐MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild‐type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2‐substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine–arginine–β‐naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.

RNA mimicry by the fap7 adenylate kinase in ribosome biogenesis.

The structure of a ribosome assembly factor in complex bound to a ribosomal protein uncovers a chaperoning function that uses RNA mimicry and is regulated by ATP hydrolysis.

Mathematical modeling in metal metabolism: Overview and perspectives

A review of mathematical modeling in metal metabolism is presented. Both endogenous and exogenous metals are considered. Four classes of methods are considered: Petri nets, multi-agent systems, determinist models based on differential equations and stochastic models. For each, a basic theoretical background is given, then examples of applications are given, detailed and commented. Advantages and disadvantages of each class of model are presented. A special attention is given to determinist differential equation models, since almost all models belong to this class.

Thiosemicarbazone modification of 3-acetyl coumarin inhibits Aβ peptide aggregation and protect against Aβ-induced cytotoxicity

Aggregation of amyloid β peptide (Aβ) is an important event in the progression of Alzheimers disease. Therefore, among the available therapeutic approaches to fight with disease, inhibition of Aβ aggregation is widely studied and one of the promising approach for the development of treatments for Alzheimers disease. Thiosemicarbazone compounds are known for their variety of biological activities. However, the potential of thiosemicarbazone compounds towards inhibition of Aβ peptide aggregation and the subsequent toxicity is little explored. Herein, we report synthesis and x-ray crystal structure of novel compound 3-acetyl coumarin thiosemicarbazone and its efficacy toward inhibition of Aβ(1-42) peptide aggregation. Our results indicate that 3-acetyl coumarin thiosemicarbazone inhibits Aβ(1-42) peptide aggregation up to 80% compared to the parent 3-acetyl coumarin which inhibits 52%. Further, 3-acetyl coumarin thiosemicarbazone provides neuroprotection against Aβ-induced cytotoxicity in SH-SY5Y cell line. These findings indicate that thiosemicarbazone modification renders 3-acetyl coumarin neuroprotective properties.