Helical antimicrobial polypeptides with radial amphiphilicity

Abstract

α-Helical antimicrobial peptides (AMPs) generally have facially amphiphilic structures that may lead to undesired peptide interactions with blood proteins and self-aggregation due to exposed hydrophobic surfaces. Here we report the design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. The radially amphiphilic structure enables the polypeptide to bind effectively to the negatively charged bacterial surface and exhibit high antimicrobial activity against both gram-positive and gram-negative bacteria. Moreover, the shielding of the hydrophobic core by the charged exterior shell decreases nonspecific interactions with eukaryotic cells, as evidenced by low hemolytic activity, and protects the polypeptide backbone from proteolytic degradation. The radially amphiphilic polypeptides can also be used as effective adjuvants, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude. Designing AMPs bearing this unprecedented, unique radially amphiphilic structure represents an alternative direction of AMP development; radially amphiphilic polypeptides may become a general platform for developing AMPs to treat drug-resistant bacteria.

Integrating Display and Delivery Functionality with a Cell Penetrating Peptide Mimic as a Scaffold for Intracellular Multivalent Multitargeting

“…21 It was anticipated that the esters would be similarly protected from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 Figure 6. Reduction of nuclear foci in the DM1 model cells were observed by treating the cells with 500 nM polymeric ligand (PLG50-1/5).…”

“…In particular, we described the first approach toward DM1 treatment that uses a polymeric delivery agent, a cell-penetrating peptide mimic, as the scaffold to bring multiple CTG-and CUG-binding agents to the target DNA and RNA within the cell. Although the cellular and in vivo fate of these macromolecular constructs is unknown, and one cannot rule out the possibility of enzymatic ester or peptide cleavage, the >100 fold increase in potency, known peptidase resistance of these polymers, 21 and demonstrated resistance to esterase cleavage is more consistent with a multivalent mode of action.…”

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

“…The vast majority of AMPs are cationic to help facilitate the targeting of microbes through direct electrostatic interaction with anionic components of their membranes [19,20]. Nearly all AMPs are also amphiphilic, which generates hydrophobic surfaces that are able to drive the partitioning of these peptides into microbial membranes and hydrophilic surfaces that are able to stabilize these hydrophobic interactions via electrostatic associations with the head group regions of these membranes [21,22]. Based on these investigations, a variety of models have been proposed to describe the antimicrobial action of AMPs with those most frequently reported appearing to be variants of the barrel-stave pore and carpet type mechanisms, which involve membrane disruption via discrete channel formation and non-specific solubilization respectively [23].…”

Bacteria‐Assisted Activation of Antimicrobial Polypeptides by a Random‐Coil to Helix Transition

“…[6] As such, the design of smart peptides with helixcoil transition provides apromising approach to enhance the selectivity of AMPs by controlling the secondary structuredependent membrane activity as well as toxicity. [8] These polypeptides adopt as table a-helical conformation with ahydrophobic interior and acharged exterior shell around the helical surface,a ffording potent antimicrobial activity closely associated with their helical structure. [8] These polypeptides adopt as table a-helical conformation with ahydrophobic interior and acharged exterior shell around the helical surface,a ffording potent antimicrobial activity closely associated with their helical structure.…”