Design of multi-functional linear polymers that capture and neutralize a toxic peptide: a comparison with cross-linked nanoparticles

Abstract

In this paper, a library of multi-functional linear poly-N-isopropylacrylamide (pNIPAm) polymers having a range of molecular weights and functional groups were synthesized and their interaction with the hemolytic peptide, melittin, was examined. The linear pNIPAm (LPs) containing both tert-butyl group and carboxylic acids bound with the peptide by a combination of hydrophobic and electrostatic interactions and neutralized its toxicity. The melittin binding capacity and affinity of each LP was quantified and further compared with cross-linked multi-functional nanogel particles (NPs) having same combination of functional groups. The binding capacity of the LPs (weight of captured melittin/weight of LP) was independent of their molecular weight and was three times higher than that of previously reported NPs.The binding constant depended on the molecular weight of the LPs, showing the highest value of 1.1 Â 10 8 (M À1 ) for a $1000 mer linear polymer with 40% tert-butyl group and 20% carboxylic acid.Comparison of the interactions of the LPs and NPs suggested the importance of the flexibility of the polymer chain in order to achieve high binding capacity and affinity.

Minimization of Synthetic Polymer Ligands for Specific Recognition and Neutralization of a Toxic Peptide

“…10,14 It has been reported that PLs with larger molecular weight shows stronger affinity to melittin than the smaller one, because the larger PLs has a higher degree of freedom in its structure and more easily map onto melittin to form high affinity binding sites. 10,14 It has been reported that PLs with larger molecular weight shows stronger affinity to melittin than the smaller one, because the larger PLs has a higher degree of freedom in its structure and more easily map onto melittin to form high affinity binding sites.…”

“…Nevertheless, 30-mer PL binds melittin strongly because of specific features in the peptide sequence, including the motif KRKR instead of KKKK, as in ponericin: Presumably, the two guanidium ions on the KRKR sequence enabled selective affinity to melittin due to strong electrostatic interaction between guanidium cation and carboxylate anion supported by two parallel hydrogen bonds. The ability of PLs to neutralize melittin toxicity was investigated by hemolysis neutralization assay (S5) 7,14 . 6 To confirm the interaction between peptide and PLs, we used isothermal titration calorimetry (ITC).…”

Design of Functional Nanoparticles for Intractable Disease Therapy

“…Additionally, typically, PPIs are larger than 1000 Å 2 and involve more than 20 amino acid contacts. 3,4) Synthetic polymers, such as dendrimers, 5) linear polymers, [6][7][8] and polymer nanoparticles (NPs), 9,10) have the potential to work as protein affinity reagents by mimicking protein-protein interactions 11) (Fig. 1b).…”

Emerging functional materials based on chemically designed molecular recognition

“…Recent studies on interactions between biomolecules and synthetic polymers reveal that polymeric nanoparticles or linear copolymers with special functions and components could exhibit high binding property and even selectivity to biomolecules like peptides, proteins and carbohydrates [40][41][42][43][44][45][46][47]. Schrader and co-work-ers first attempted to synthesize a library of random statistical linear copolymers for the discovery of protein affinity [40].…”