1.D.28 The Lipopeptaibol (Lipopeptaibol) Family
Lipopeptaibols are members of a family of naturally occurring, short peptides with antimicrobial activity, characterized by a lipophilic acyl chain at the N-terminus, a high content of turn/helix inducing alpha-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. Using solution methods, the prototypical lipopeptaibol trichogin GA IV and a large series of appropriately designed analogues have been synthesized, which allowed: (i) determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity (Peggion et al., 2003). Physico-chemical techniques were used, to assess the trichogin preferred conformation under a variety of conditions and estimate its mechanism of interaction with the phospholipid membranes.
De Zotti et al. (2009) have evaluated the antibacterial and hemolytic activities of the amphiphilic helical, membrane-active, lipopeptaibol trichogin GA IV and its [Leu(11)-OMe] analogue. They were compared to those of the partially helical or non-helical 8-meric or 4-meric, C-terminal short sequences, respectively. The study was conducted in part with several methicillin-resistant Staphylococcus aureus strains. The resistance to proteolysis of these peptides was also evaluated (De Zotti et al., 2009).
The lipopeptaibol trichogin GA IV is a natural, non-ribosomally synthesized, antimicrobial peptide resistant to the action of hydrolytic enzymes which contains the non-coded residue α-aminoisobutyric acid (Aib), which is known to be responsible for the adoption of particularly stable helical structures in other short peptides. To investigate the role of Aib residues on the 3D-structure and bioactivity of trichogin GA IV, De Zotti et al. (2012) synthesized and fully characterized four analogs where one or two Aib residues are replaced by L-Leucine. Conformational studies (including an X-ray diffraction analysis) and biological assays performed on these analogs showed that the Aib to L-Leucine replacements did not affect the resistance to proteolysis, but modulated the bioactivity of trichogin GA IV in a 3D-structure related manner. The transmembrane peptide channel form is stabilized by cholesterol (Syryamina et al. 2012).
Trichogin GA IV (TCG) was incorporated in the lipid bilayer moiety of a mercury-supported tethered bilayer lipid membrane (tBLM) at a non-physiological transmembrane potential of about -240mV, negative on the trans side of the bilayer (Becucci et al., 2012). Once incorporated in the tBLM, TCG was stable over the range of physiological transmembrane potentials and permeabilized the membrane at transmembrane potentials negative of -80÷-90mV. The chronocoulometric behavior was consistent with the kinetics of nucleation and growth of bundles of TCG building blocks with ion-channel properties. The TCG building blocks also permeabilize the lipid bilayer at more negative transmembrane potentials, and could be regarded as dimers of aligned TCG helical monomers. The cyclic voltammograms of tBLMs incorporating TCG point to voltage-gated behavior of the TCG channel, similar to that exhibited by the peptaibol alamethicin (Becucci et al., 2012). Dzuba & Raap (2013) used spin-echo EPR to study the pore-formation on lipopeptaibol in model and bacterial membranes.
The generalized reaction catalyzed by lipopeptaibols such as trichogin GA IV is:
ions (in) ⇌ ions (out)