Conformational properties of secondary amino acids: Replacement of pipecolic acid by N-methyl-L-alanine in efrapeptin C

The efrapeptins, a family of naturally occurring peptides with inhibitory activities against ATPases, contain several α,α-disubstituted α-amino acids such as α-aminoisobutyric acid (Aib) or isovaline (Iva) besides pipecolic acid (Pip), β-Ala, Leu, Gly, and a C-terminal heterocyclic residue. Secondary α-amino acids such as proline are known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-alkyl α-amino acids. We synthesized two efrapeptin C analogs with replacement of Pip by N-methyl-L-alanine (MeAla) using a combination of solid- and solution-phase techniques in a fragment-condensation strategy to compare the conformational bias of both secondary amino acids. The solution conformation was investigated by vibrational circular dichroism (VCD) to probe whether the analogs adopt a 3₁₀-helical conformation. The MeAla-containing analogs [MeAla^1,3]efrapeptin C and [MeAla^1,3,11]efrapeptin C inhibit ATP hydrolysis by the A₃B₃ complex of A ₁A₀-ATP synthase from Methanosarcina mazei Gö1.