Improved solid‐phase synthesis of α,α‐dialkylated amino acid‐rich peptides with antimicrobial activity*

Abstract

A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid-phase synthetic techniques. Each nonapeptide was rich in alpha,alpha-dialkylated amino acids [one 4-aminopiperidine-4-carboxylic acid (Api) and six alpha-aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9-fluorenylmethyloxycarbonyl (Fmoc)-Aib-Aib-OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 3(10)-helical, amphipathic design of these peptides was born out most prominently in the N-terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations < or =100 microM) and the acetylated peptides (concentrations < or = 200 microM) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages.

Chirality and helix stability of polyglutamic acid enantiomers

“…The intensity of the n → π * transition/absorption band at 222-225 nm is related to the content of the α-helix while that of π → π * transition/absorption band at 205-209 nm is related to the 3 10 -form [15,17,[27][28][29][30]. The intensity of absorption is expressed by the mean molar ellipticity [θ ] in units (deg cm 2 /dmol) and the ratio R = [θ ] n→π * /[θ ] π→π * can be used for the estimation of the two helical forms: For R 1, the helix is of the α-form, while for R ≈ 0.4 the helix has of the 3 10 -configuration.…”

“…The α-helix and the 3 10 -helical forms of polyaminoacids bear very distinct fingertips in the circular dichroism (CD) spectra [15,17,[27][28][29][30]. Namely, they adsorb light in the UV range at 222-225 nm (n → π * transition) and at 205-209 nm (π → π * transition), respectively.…”

“…The resulting macromolecular proteins which are the cornerstones of life, if find themselves in conditions of pH, solvents, temperature, etc. suitable for formation of helices, obtain the conformation of right-hand or α-helix [13][14][15][16][17][18][19][20]. So, the development of right-hand α-helix is the result of successive bonding of L-type aminoacids to each other via peptide ==CO-HN== bonds.…”

Enhanced and Prolonged Cell-Penetrating Abilities of Arginine-Rich Peptides by Introducing Cyclic α,α-Disubstituted α-Amino Acids with Stapling

“…Peptides containing cyclic dAAs prefer to form helical structures 23−25 and have been reported as helical functional peptides such as peptide catalysts 26−28 and antimicrobial peptides. 29,30 We expected the synergistic effects between the introduction of cyclic dAAs and the staple in Arg-rich peptides to improve their helicities in aqueous solution and cell-penetrating abilities for a long time.…”

Plasmid DNA Delivery Using Cell-Penetrating Peptide Foldamers Composed of Arg–Arg–Aib Repeating Sequences

“…Aib has been discovered in a number of natural antimicrobial peptides as building blocks − and is well-known to stabilize peptide helical secondary structures. − Owing to its usefulness, a variety of types of protected Aib are commercially available. Aib has been widely used as a helix inducer for the design and synthesis of functional helical peptide foldamers, such as antimicrobial peptides, − bioactive peptides, , and peptide catalysts. , Cell-penetrating peptides (CPPs), which can deliver membrane-impermeable compounds into living cells, are also one of the targets of Aib-containing peptide foldamers. , …”