Helical Antimicrobial Peptide Foldamers Containing Non‐proteinogenic Amino Acids

Abstract

Antimicrobial peptides (AMPs) are potential novel therapeutic drugs against microbial infections. Most AMPs function by disrupting microbial membranes because of their amphipathic properties and ordered secondary structures. In this minireview, we describe recent efforts to develop helical AMP foldamers containing non-proteinogenic amino acids, such as α,α-disubstituted α-amino acids, β-amino acids, γ-amino acids, side-chain stapling and N-alkyl glycines.

Flat, Cα,β‐Didehydroalanine Foldamers with Ferrocene Pendants: Assessing the Role of α‐Peptide Dipolar Moments

“…However, efforts are continuously made also to mimic protein functions, but using β‐, γ‐ and δ‐amino acids, [3e,4] as well as other non‐coded α‐amino acids [5] . These residues are investigated for a variety of reasons: they impart enzymatic resistance to the peptides where they are inserted; [5j] they are contained in bioactive natural products; [5k] they increase peptide structural rigidity; [4] they are useful tools to build new 3D‐structures; [4b,5b] they can be exploited in bio‐organic and supramolecular chemistry [5c–e,j] …”

The antibacterial activity of peptide dendrimers and polymyxin B increases sharply above pH 7.4

“…1 ). 9–11 Similar to many antimicrobial peptides (AMPs), 12–15 polymers, 16 peptidomimetics 17 and foldamers, 18 our peptide dendrimers act by a membrane disruptive mechanism, 19 which in our case involves α-helical folding of the amphiphilic dendrimer core in contact with the bacterial membrane. 20 …”

“…In summary, although the pH-dependence of activity of AMPs and small molecule antibiotics was well documented, 24,27,28,30,31 our study revealed a previously unknown activity increase between pH 7.4 and pH 8.0 against K. pneumoniae and MRSA with AMPDs and PMB . pH-profiling of polycationic AMPs and analogs such as dendrimers, 4 polymers, 16 peptidomimetics 17 and foldamers 18 might reveal related effects and increase the application potential of such compounds, in particular when considering topical treatment where local buffering can be considered.…”

A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

“…1). [9][10][11] Similar to many antimicrobial peptides (AMPs), [12][13][14][15] polymers, 16 peptidomimetics 17 and foldamers, 18 our peptide dendrimers act by a membrane disruptive mechanism, 19 which in our case involves a-helical folding of the amphiphilic dendrimer core in contact with the bacterial membrane. 20 G3KL and T7 possess eight N-termini with a depressed pK a of B6.5 due to multivalency, implying that, as for related transfection dendrimers, 21,22 the number of positive charges strongly increases at acidic pH.…”

“…In summary, although the pH-dependence of activity of AMPs and small molecule antibiotics was well documented, 24,27,28,30,31 our study revealed a previously unknown activity increase between pH 7.4 and pH 8.0 against K. pneumoniae and MRSA with AMPDs and PMB. pH-profiling of polycationic AMPs and analogs such as dendrimers, 4 polymers, 16 peptidomimetics 17 and foldamers 18 might reveal related effects and increase the application potential of such compounds, in particular when considering topical treatment where local buffering can be considered.…”