Nα,δ-Bis-Fmoc-L-ornithine

BACKGROUNDDysregulation of l-arginine metabolism has been proposed to occur in patients with severe asthma. The effects of l-arginine supplementation on l-arginine metabolite profiles in these patients are unknown. We hypothesized that individuals with severe asthma with low fractional exhaled nitric oxide (FeNO) would have fewer exacerbations with the addition of l-arginine to their standard asthma medications compared with placebo and would demonstrate the greatest changes in metabolite profiles.METHODSParticipants were enrolled in a single-center, crossover, double-blind l-arginine intervention trial at UCD. Subjects received placebo or l-arginine, dosed orally at 0.05 mg/kg (ideal body weight) twice daily. The primary end point was moderate asthma exacerbations. Longitudinal plasma metabolite levels were measured using mass spectrometry. A linear mixed-effect model with subject-specific intercepts was used for testing treatment effects.RESULTSA cohort of 50 subjects was included in the final analysis. l-Arginine did not significantly decrease asthma exacerbations in the overall cohort. Higher citrulline levels and a lower arginine availability index (AAI) were associated with higher FeNO (P = 0.005 and P = 2.51 × 10-9, respectively). Higher AAI was associated with lower exacerbation events. The eicosanoid prostaglandin H2 (PGH2) and Nα-acetyl-l-arginine were found to be good predictors for differentiating clinical responders and nonresponders.CONCLUSIONSThere was no statistically significant decrease in asthma exacerbations in the overall cohort with l-arginine intervention. PGH2, Nα-acetyl-l-arginine, and the AAI could serve as predictive biomarkers in future clinical trials that intervene in the arginine metabolome.TRIAL REGISTRATIONClinicalTrials.gov NCT01841281.FUNDINGThis study was supported by NIH grants R01HL105573, DK097154, UL1 TR001861, and K08HL114882. Metabolomics analysis was supported in part by a grant from the University of California Tobacco-Related Disease Research Program program (TRDRP).

Backbone-cyclized peptides and peptidomimetics integrate the biological activity and pharmacological features necessary for successful research tools and therapeutics. In general, these structures demonstrate improved maintenance of bioactive conformation, stability and cell permeability compared to their linear counterparts, while maintaining support for a variety of side chain chemistries. We explain how backbone cyclization and cycloscan techniques allow scientists to cyclize linear peptides with retained or enhanced biological activity and improved drug-like features. We discuss head-to-tail (Cterminus to N-terminus), building unit-to-tail, building unit-to-side chain, building unit-to-building unit, and building unit-to-head backbone cyclization, with examples of building blocks, such as Nα-(ω- thioalkylene), Nα-(ω-aminoalkylene) and Nα-(ω-carboxyalkylene) units. We also present several methods for recombinant expression of backbone-cyclized peptides, including backbone cyclic peptide synthesis using recombinant elements (bcPURE), phage display and induced peptidyl-tRNA drop-off. Moreover, natural backbone-cyclized peptides are also produced by cyanobacteria, plants and other organisms; several of these compounds have been developed and commercialized for therapeutic applications, which we review. Backbone-cyclized peptides and peptidomimetics comprise a growing share of the pharmaceutical industry and will be applied to additional problems in the near future.

Short and ultra-short peptides have been recently envisioned as excellent building blocks for the formulation of hydrogels with appealing properties. Due to its simplicity and capability to gel under physiological conditions, Fmoc-FF (Nα-fluorenylmethoxycarbonyl-diphenylalanine), remains one of the most studied low molecular-weight hydrogelators. Since its first identification in 2006, a plethora of its analogues were synthetized and investigated for the fabrication of novel supramolecular materials. Here we report a description of the Fmoc-FF analogues in which the aromatic Fmoc group is replaced with other substituents. These analogues are distinguished into five different classes including derivatives: i) customized with solid phase peptide synthesis protecting groups; ii) containing non-aromatic groups, iii) containing aromatic groups, iv) derivatized with metal complexes and v) containing stimuli-responsive groups. The morphological, mechanical, and functional effects caused by this modification on the resulting material are also pointed out.