Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers

Mowery, Brendan P.; Lee, Sarah E.; Kissounko, Denis A.; Epand, Richard M.; Weisblum, Bernard; Stahl, Shannon S.; Gellman, Samuel H.

doi:10.1021/ja077288d

Cited by 421 publications

(465 citation statements)

References 31 publications

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“…The globally amphiphilic conformation could perform the key roles for considerable antimicrobial activity, as shown in Figure 5. 64 It is found that higher ratio of cationic groups can benefit to reduce the hemolytic effect, while higher ratio of hydrophobic groups is of great importance for antimicrobials. They utilized minimum hemolytic concentration to display biocompatibility of antimicrobial cationic polymers.…”

Section: Induced Globally Amphiphilic Conformationmentioning

confidence: 99%

Antimicrobial cationic polymers: from structural design to functional control

Yang

Cai

Huang

et al. 2017

Polym J

212

174

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Antimicrobial cationic polymers mainly contain two functional components: the cationic groups and the hydrophobic groups. The antimicrobial activity is influenced by the type, amount, location and distribution of these two components. This review summarizes the designs and syntheses of antimicrobial cationic polymers by controlling the above two factors. It involves the structural designs from primary to secondary structures, from covalent to noncovalent syntheses and from bulk to surface. Furthermore, it will discuss how to advance structural designs toward functional controls for optimizing the antimicrobial performances and biocompatibility of antimicrobial cationic polymers. It is anticipated that this review will provide some guidelines for developing molecular engineering of antimicrobial cationic polymers with tailor-made structures and functions.

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Section: Induced Globally Amphiphilic Conformationmentioning

confidence: 99%

Antimicrobial cationic polymers: from structural design to functional control

Yang

Cai

Huang

et al. 2017

Polym J

212

174

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“…Upon binding to membranes, they often organize as α-helices with hydrophobic and hydrophilic residues on opposite faces, a feature referred to as secondary amphipathic character. Designers of synthetic CAPs found that it was possible to modify CAP activity towards microbial and mammalian cells independently by varying the hydrophobicity, as well as the number and the position of the positive charges in the amphiphilic structure [3][4][5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

“…Melittin-21Q exhibited a reduced or similar binding to DMPC and to DMPG bilayers compared to native melittin, suggesting a favorable or a limited contribution of the cationic C-terminal portion to membrane affinity. Another investigation, using tryptophan fluorescence, revealed that melittin and its Cterminal truncated versions , and [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], all showed an increased affinity for 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) 70/30 large unilamellar vesicles (LUVs) compared POPC LUVs 47 (See Supporting Information). These findings highlighted the role of attractive electrostatic interactions.…”

Section: Introductionmentioning

confidence: 99%

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

2016

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The widespread distribution of cationic antimicrobial peptides capable of membrane fragmentation in nature underlines their importance to living organisms. In the present work, we determined the impact of the electrostatic interactions associated with the cationic Cterminal segment of melittin, a 26-amino acid peptide from bee venom (net charge +6), on its binding to model membranes and on the resulting fragmentation. In order to detail the role played by the C-terminal charges, we prepared a melittin analogue for which the 4 cationic amino acids in positions 21 to 24 were substituted with the polar residue citrulline, providing a peptide with the same length and amphiphilicity but with a lower net charge (+2). We compared the peptide bilayer affinity and the membrane fragmentation for bilayers prepared from dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS) mixtures. It is shown that neutralization of the C-terminal considerably increased melittin affinity for zwitterionic membranes. The unfavorable contribution associated with transferring the cationic C-terminal in a less polar environment was reduced, leaving the hydrophobic interactions, which drive the peptide insertion in bilayers, with limited counterbalancing interactions. The presence of negatively charged lipids (DPPS) in bilayers increased melittin binding by introducing attractive electrostatic interactions, the augmentation being, as expected, greater for native melittin than for its citrullinated analogue. The membrane fragmentation power of the peptide was shown to be controlled by electrostatic interactions and could be modulated by the charge carried by both the membrane and the lytic peptide. The analysis of the lipid composition of the extracted fragments from DPPC/DPPS bilayers revealed no lipid specificity. It is proposed that extended phase separations are more susceptible to lead to the extraction of a lipid species in a specific manner than a specific lipid-peptide affinity. The present work on the lipid extraction by melittin and citrullinated melittin with model membranes emphasizes the complex relation between the affinity, the lipid extraction/membrane fragmentation, and the lipid specificity.

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“…There has also been growing interest in synthetic polymer-based AMP mimics bearing both cationic and hydrophobic groups, which can be prepared through cost-effective polymerization processes. For example, simplified polymeric AMP analogs have been developed, including poly (methacrylamides) (31), poly(β-lactams) (14,(32)(33)(34)(35), polypeptides (36)(37)(38), poly(norborenes) (39,40), and poly(carbonates) (41,42). These compounds are considerably less expensive than peptides, and much work is being done to optimize them.…”

mentioning

confidence: 99%

Helical antimicrobial polypeptides with radial amphiphilicity

Xiong

Lee

Mansbach

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

190

143

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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.

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Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers

Cited by 421 publications

References 31 publications

Antimicrobial cationic polymers: from structural design to functional control

Antimicrobial cationic polymers: from structural design to functional control

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

Helical antimicrobial polypeptides with radial amphiphilicity

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