Peptaibiotic folding and bioactivity: role of backbone endothioamide linkages

A common tool to bias the conformation of linear peptides is the insertion of side-chain modified amino acids or sidechain/main-chain conformationally restricted building blocks. An alternative approach is a simple backbone modification. In this connection, backbone amide replacements with (almost) isosteric surrogates were extensively used. These modifications may impart resistance to enzymatic degradation and better bioavailability to the peptides, but also influence the secondary structure. A thioamide (?[CS-NH]) is perhaps the closest structural mimic of an amide. However, it possesses different and attractive features: (i) Its NH group forms stronger hydrogen bonds, being more acidic than that of the amide. (ii) Its C-N bond undergoes cis/trans isomerization by irradiation at 260 nm (?->?* transition). (iii) It may act as a "minimalist" fluorescence quencher. For all these reasons, we started a programme aimed at exploring how the endothioamide bond affects peptide folding and bioactivity. In this communication, we describe the synthesis and conformational results of the three analogs of the membrane-active peptaibiotic trichogin GA IV listed below: n-octanoyl-Aib-Gly-?[CS-NH]-Leu-Aib-Gly-Gly-Leu-Aib-Gly-Ile-Leu-OMe (2/3) n-octanoyl-Aib-Gly-Leu-Aib-Gly-?[CS-NH]-Gly-Leu-Aib-Gly-Ile-Leu-OMe (5/6) n-octanoyl-Aib-Gly-Leu-Aib-Gly-Gly-Leu-Aib-Gly-?[CS-NH]-Ile-Leu-OMe (9/10) The syntheses of the three peptides were accomplished in solution according to a fragment condensation approach. Appropriate thioamide-containing tri- or tetrapeptides were prepared by treating the corresponding all-amide precursors with the Lawesson reagent. FT-IR absorption, 2D-NMR and CD conformational investigations on the three analogs were conducted in comparison with the naturally occurring peptaibiotic. All three analogs maintain the capability to interact with the DOPE/DOPG model phospholipid membranes and exhibit a comparable bioactivity against S. aureus.