Structure−activity Relationships among Random Nylon-3 Copolymers That Mimic Antibacterial Host-Defense Peptides

Abstract

Host-defense peptides are natural antibiotics produced by multicellular organisms to ward off bacterial infection. Since the discovery of these molecules in the 1980s, a great deal of effort has been devoted to elucidating their mechanisms of action and to developing analogues with improved properties for possible therapeutic use. The vast majority of this effort has focused on materials composed of a single type of molecule, most commonly a peptide with a specific sequence of alpha-amino acid residues. We have recently shown that sequence-random nylon-3 copolymers can mimic favorable properties of host-defense peptides, and here we document structure-activity relationships in this polymer family. Although the polymers are heterogeneous in terms of subunit order and stereochemistry, these materials display structure-activity relationships comparable to those that have been documented among host-defense peptides and analogous synthetic peptides. Previously such relationships have been interpreted in terms of a specific and regular folding pattern (usually an alpha-helix), but our findings show that these correlations between covalent structure and biological activity do not require the adoption of a specific or regular conformation. In some cases our observations suggest alternative interpretations of results obtained with discrete peptides.

Antimicrobial Polymers: Mimicking Amino Acid Functionali ty, Sequence Control and Three-dimensional Structure of Host-defen se Peptides

“…This is nicely demonstrated for nylon-3 copolymers where a small change in dispersity (at constant molar mass) shows tremendous increase in haemolysis (Ð = 1.06, HC 50 = 800 µg mL -1 ; Ð = 1.15, HC 50 = 12.5 µg mL -1 ). 27 It was confirmed by dialysis experiments that the higher molecular weight fractions cause the toxicity. This demonstrates the importance of the molar mass in this context and the necessity for controlled polymerization techniques in order to draw structure property relationships.…”

“…26 The monomer architecture was also varied (i.e. variation in alkyl ring size 27 or cyclic vs. non-cyclic 28 ) and it was concluded that an excess of hydrophobicity (i.e. by larger alkyl ring sizes) results in increased hemolytic activity and loss of antimicrobial activity (presumably by ineffective membrane attachment).…”

“…by larger alkyl ring sizes) results in increased hemolytic activity and loss of antimicrobial activity (presumably by ineffective membrane attachment). 27 However, the backbone flexibility seems to also play a role as a non-cyclic monomer with the same number of carbon atoms showed improved biological activity. 29 …”

“…Many studies have considered the structure-property relationship and have come to the conclusion that the DP of an AMP mimic should be low, preferably below 30 (it is noteworthy that AMPs are typically less than 45 amino acids long 13a ), independently of the nature of the polymer, being methacrylates, 17a, 37 nylon-3 polymers, 27 and poly(norbornenes). 22b For some examples, longer polymeric chains maintain their activity against bacteria, while the ability to destroy red blood cells increases, 27,38 for other polymeric systems also antimicrobial activity scales with the molecular weight. 22b, 27 This was investigated in detail for norbornene polymers with small variations in molar mass.…”

“…22b For some examples, longer polymeric chains maintain their activity against bacteria, while the ability to destroy red blood cells increases, 27,38 for other polymeric systems also antimicrobial activity scales with the molecular weight. 22b, 27 This was investigated in detail for norbornene polymers with small variations in molar mass. Indeed, it was shown that while monomeric units did not show any activity, oligomers did kill bacteria.…”