Reprogramming the Biosynthesis of Cyclodepsipeptide Synthetases to Obtain New Enniatins and Beauvericins.

Non-ribosomal peptide synthetases are complex multimodular biosynthetic machines that assemble various important and medically relevant peptide antibiotics. An interesting subgroup comprises the cyclodepsipeptide synthetases from fungi synthesizing cyclohexa- and cyclo-octadepsipeptides with antibacterial, anthelmintic, insecticidal, and anticancer properties; some are marketed drugs. We exploit the modularity of these highly homologous synthetases by fusing the hydroxy-acid-activating module of PF1022 synthetase with the amino-acid-activating modules of enniatin and beauvericin synthetase, thus yielding novel hybrid synthetases.

Selective indole-based ECE inhibitors: synthesis and pharmacological evaluation.

Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 led to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group.

Novel, selective indole-based ECE inhibitors: lead optimization via solid-phase and classical synthesis.

A novel class of indole-based endothelin-converting enzyme (ECE) inhibitors was identified by high throughput screening. We report systematic optimization of this compound class by means of classical and solid-phase chemistry. Optimized compounds with a bisarylamide side chain at the 2-position of the indole skeleton exhibit low-nanomolar activity on ECE.

Evaluation of synchronous twin pulse technique for shock wave lithotripsy: determination of optimal parameters for in vitro stone fragmentation.

Purpose: The Twinheads extracorporeal shock wave lithotriptor (THSWL) is composed of 2 identical shock wave generators and reflectors. One reflector is under the table and the other is over the table with a variable angle between the axes of the 2 reflectors. The 2 reflectors share a common second focal point, making it possible to deliver an almost synchronous twin pulse to the targeted stone.

Comparison of blood group versus HLA-dependent transplantation and its influence on donor kidney survival.

Background: The advantages of organ allocation based on human leukocyte antigen (HLA) typing are controversial. This evaluation compares the results of HLA-dependent and non-HLA-dependent allocation in the transplantation of donor kidneys.

Methods: Seventy-seven donor kidney pairs explanted locally between 1984 and 1994 were examined.