Serine-, threonine-, and cysteine-derived cyclic building blocks (pseudo-prolines, ΨPro) serve as reversible protecting groups for Ser, Thr, and Cys and prove to be versatile tools for overcoming some intrinsic problems in the field of peptide chemistry. The presence of ΨPro within a peptide sequence results in the disruption of β-sheet structures considered as a source of intermolecular aggregation during chain elongation, thus increasing solvation and coupling kinetics in peptide assembly. Due to their easy synthetic access and variability in the chemical stability by modifications introduced in the C-2 position of the oxazolidine/thiazolidine ring system, this protection technique is adaptable to all common strategies in peptide synthesis. We describe new types of ΨPro building blocks suitable for standard Fmoc/tBu-based solid phase peptide synthesis, convergent strategies, and chemoselective ligation techniques as well as their use as a structure-disrupting, solubilizing protection technique for the example of peptides generally considered as “difficult sequences”.

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The emergence of resistance to existing antibiotics demands the development of novel antimicrobial agents directed against novel targets. Historically, bacterial cell wall synthesis, protein, and DNA and RNA synthesis have been major targets of very successful classes of antibiotics such as beta-lactams, glycopeptides, macrolides, aminoglycosides, tetracyclines, rifampicins and quinolones. Recently, efforts have been made to develop novel agents against validated targets in these pathways but also against new, previously unexploited targets. The era of genomics has provided insights into novel targets in microbial pathogens. Among the less exploited--but still promising--targets is the family of 20 aminoacyl-tRNA synthetases (aaRSs), which are essential for protein synthesis. These targets have been validated in nature as aaRS inhibition has been shown as the specific mode of action for many natural antimicrobial agents synthesized by bacteria and fungi. Therefore, aaRSs have the potential to be targeted by novel agents either from synthetic or natural sources to yield specific and selective anti-infectives. Numerous high-throughput screening programs aimed at identifying aaRS inhibitors have been performed over the last 20 years. A large number of promising lead compounds have been identified but only a few agents have moved forward into clinical development. This review provides an update on the present strategies to develop novel aaRS inhibitors as anti-infective drugs.

N6022 is a novel, first-in-class drug with potent inhibitory activity against S-nitrosoglutathione reductase (GSNOR), an enzyme important in the metabolism of S-nitrosoglutathione (GSNO) and in the maintenance of nitric oxide (NO) homeostasis. Inhibition of GSNOR by N6022 and related compounds has shown safety and efficacy in animal models of asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease [Sun, X., et al. (2011) ACS Med. Chem. Lett. 2, 402-406]. N6022 is currently in early phase clinical studies in humans. We show here that N6022 is a tight-binding, specific, and fully reversible inhibitor of GSNOR with an IC(50) of 8 nM and a K(i) of 2.5 nM. We accounted for the fact that the NAD(+)- and NADH-dependent oxidation and reduction reactions, catalyzed by GSNOR are bisubstrate in nature in our calculations. N6022 binds in the GSNO substrate binding pocket like a competitive inhibitor, although in kinetic assays it behaves with a mixed uncompetitive mode of inhibition (MOI) toward the GSNO substrate and a mixed competitive MOI toward the formaldehyde adduct, S-hydroxymethylglutathione (HMGSH). N6022 is uncompetitive with cofactors NAD(+) and NADH. The potency, specificity, and MOI of related GSNOR inhibitor compounds are also reported.