Synthesis, and Structural and Biological Studies of Efrapeptin C Analogues

Abstract

A series of analogues of efrapeptin C (1), with variations in the central tripeptide epitope (positions 6-8), were prepared by a combination of solid- and solution-phase peptide syntheses. The conformations of the modified compounds 2-6 were investigated by circular-dichroism (CD) spectroscopy to differentiate between 3(10)- and alpha-helical secondary structures. The inhibitory activities of the new compounds towards F(1)-ATPase from E. coli were determined. The modified congeners 3-5 were less active by one order of magnitude compared to 1 (K(i) 10 microM), and 6 was completely inactive. Our experiments demonstrate that the flexible, central tripeptide epitope, comprising positions 6-8 in 1, is crucial for molecular recognition, even slight sequence modifications being hardly tolerated.

Synthesis, preferred conformation, protease stability, and membrane activity of heptaibin, a medium‐length peptaibiotic

“…Peptaibiotics are tipically divided in three subclasses, depending upon the length of their primary structure: (i) short‐sequence (less than 11 residues), such as trichogin GA IV2, 3, characterized by a long fatty acyl moiety at the N‐terminus; (ii) long‐sequence (e.g. alamethicin)4, with 17–21 residues; and (iii) medium‐length (14–16 residues), such as among others antiamoebin5, efrapeptin6, and tylopeptin7. Despite the interesting antibiotic and antifungal properties exhibited by these last membrane‐active peptides, their exact mechanism of action is still unknown.…”

Synthesis and Conformational Analysis of Efrapeptins

“…Efrapeptin is reported to bind to the soluble bovine F 1 -ATPase with a K d % 10 À8 m. [43] Electronic CD spectroscopy: The solution conformation of synthetic efrapeptin C and some analogues was analyzed by CD spectroscopy (Figure 2-3). [36] Likewise, all native ( Figure 2) and synthetic efrapeptin analogues (Figure 3) gave rise to negative CD bands at 203-206 nm (p!p*) and at 225-235 nm (n!p*) that were assigned to helical conformations. The CD signatures have similarity to those of the bIII turn, [44] which is the basic element of the 3 10 -helix, or the b-bend ribbon, [45] which chiroptically behaves as a subtype of the 3 10 -helix.…”

“…[29] The reduction takes place at room temperature, can easily be monitored also during solid-phase peptide synthesis on the resin by FT-IR-spectroscopy and was found to be complete in a few minutes. The success of this synthetic approach has for the first time been demonstrated for efrapeptin C [29] and for the synthesis of efrapeptin C analogues [35,36] to be examined for bioactivity and conformational preferences in order to derive structure-activity relationships. Because of the acid lability of Aib À Pip bonds-similar to the Aib À Pro peptide bond [37] -employment of the highly acid sensitive o-chlorotrityl resin turned out to be most suitable for solid-phase peptide synthesis.…”

“…However, the latter two, being C www.chemeurj.org proaches with a different degree of convergence for the synthesis of most of the efrapeptins and their analogues. The first approach that was used for efrapeptin C [29] and some analogues [35,36] comprises fragment coupling of the N-terminal octapeptide fragment 5 (Pip 1 -Gly 8 , Scheme 2) with a Cterminal octapeptide fragment 10 including the amino acidderived cap X (Scheme 5). The latter was obtained by condensation of a central fragment 8 (Aib 9 -Gly 13 , Scheme 4) with Leu 14 -Aib 15 -X (7), synthesized according to Scheme 3.…”

Sequences of Acretocins, Peptaibiotics Containing the Rare 1‐Aminocyclopropanecarboxylic Acid, from Acremonium crotocinigenum CBS 217.70

“…Notably, the challenging synthesis of the C‐terminal X 16 residue has also been achieved . Continuation of this approach using combined solid‐ and solution‐phase synthesis of peptide segments provided efrapeptins D–G and analogs, which also contain l ‐Iva …”