Multicopper Clusters Catalyze the Oxidative Phenol Macrocyclization (OxPM) of Linear Peptides

The biosynthesis of glycopeptide antibiotics such as vancomycin and other biologically active biaryl-bridged and diaryl ether-linked macrocyclic peptides includes key enzymatic oxidative phenol macrocyclization(s) of linear precursors. However, a simple and step-economical biomimetic version of this transformation remains underdeveloped. Here, we report highly efficient conditions for preparing biaryl-bridged and diaryl ether-linked macrocyclic peptides based on multicopper(II) catalysts. The selective syntheses of ring models of vancomycin and the arylomycin cyclic core illustrate the potential of this technology to facilitate the assembly of complex antibiotic macrocyclic peptides whose syntheses are considered highly challenging. The unprecedented ability of multicopper clusters to chelate tethered diphenols and promote intramolecular over intermolecular coupling reactions demonstrates that copper clusters can catalyze redox transformations that are not accessible by smaller metal catalysts

Dynamic changes in HCV RNA levels and viral quasispecies in a patient with chronic hepatitis C after telaprevir-based treatment

Background: Telaprevir is a selective inhibitor of the hepatitis C virus NS3 center dot 4A serine protease. Treatment with telaprevir resulted in a rapid HCV-RNA decline in chronic hepatitis C genotype 1 patients. Objectives: To report the clinical and viral course of a patient treated with telaprevir in combination with pegylated interferon-alpha-2a and ribavirin in a Phase 2 clinical trial (PROVE3). Study design: This previous non-responder to interferon based therapy was treated for 40 weeks with a telaprevir, pegylated interferon alpha-2a, and ribavirin regimen. Viral sequencing and phylogenetic analysis were performed before, during and after therapy. Results: The patient, a 54 years old male patient, experienced a viral relapse 4 weeks post-treatment and HCV-RNA levels continued to increase 14 weeks post-treatment (150,000 IU/mL). The viral population, which was wild type at baseline, consisted of only V36A variants at both of these post-treatment time-points. Subsequently, this patient had a transient disappearance of HCV-RNA for more than 1 year in the absence of antiviral therapy. Thereafter, HCV-RNA reappeared again with a viral population consisting of only wild type virus. Phylogenetic analysis of NS3 center dot 4A corresponded with a viral population bottleneck resulting in changes in viral quasispecies. Conclusion: In this case report, significant viral load reductions resulted in a genetic bottleneck leading to a reduction of variability in the hepatitis C viral population. We hypothesize that the reduction in viral heterogeneity potentially led to a reduced viral capacity to adapt to a host immune response leading to a transient loss of detectable HCV-RNA. (C) 2011 Elsevier B.V. All rights reserve

Metalloprotease type III effectors that specifically cleave JNK and NF-κB

Enteropathogenic E. coli secretes multiple effector proteins that enable host-cell colonization. Two effectors, NleC and NleD, are here shown to act as endopeptidases, cleaving p65 and JNK to inhibit the inflammatory response