Thiolactone peptides

Therapeutic profile In mimicking the quorum-sensing peptides, the thiolactone peptides act as antibacterials, naturally regulating the growth of the bacteria. 

Synthetic highlights This chapter describes the background for the development of modem peptide syntheses. This involves chemical ligation of unprotected peptides carried out with chaotropes. Using a transient thioester-linked intermediate, native chemical ligation (NCL) of two unprotected peptides is achieved. With Fmoc protecting groups and the use of Rink resin, chemoselectivity of peptide synthesis is feasible. The development of NCL, as applied to thiolactone peptide synthesis, is considered in detail. 

This compound is a cyclic, non-natural peptide with a thiolactone unit and a representative of the group of cyclic peptide inhibitors of staphylococcal virulence. Thiolactone peptides are expected to act as anti-bacterial therapeutics by a highly specific mechanism, as outlined in the following sections. 

As mentioned in the introduction to this chapter, the recent discovery of thiolactone peptides as potential antimicrobial agents, based on flieir ability to act as antagonists of natural auto-inducing peptides (AIP), prompted the new synthetic achievements, which permitted the synthesis of these cyclic peptide inhibitors. Here, we discuss the most recent achievement in the synthesis of AIP mimics, based on an original linker for the Fmoc-based solid-phase methodology. 

Previous AIP syntheses involved a combined solid-phase solution route. According to this new method, a linear unprotected peptide, a-thioester XI, prepared by f rf-butoxycarbonyl (tert-Boc)-SPPS undergoes cycUzation to XII through trani-thioesterification, and elimination of the resin in aqueous buffer to yield the thiolactone peptide XIII (Scheme 12.5) [36]. 

Scheme 12-5 Schematic presentation of the synthesis of thiolactone peptide Xni with N-Boc protected amino acids (modified fi-om [36])...

SPPS of the thiolactone peptide precursor 22 was completed by sequential addition of N-Fmoc protected AAs (Phe, Lys, Ser, Ser and Cys). This sequence is presented in Scheme 12.10. 

Scheme 12.10 SPPS of 22, the acyclic precursor of the thiolactone peptide 1...

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