Peptoid microsphere coatings: The effects of helicity, temperature, pH, and ionic strength

Abstract

Peptoids are peptidomimetic oligomers that predominantly harness similarities to peptides for biomimetic functionality. They have potential for use in biomedical applications and biosensors due to resistance to proteolytic degradation and low immunogenicity. The incorporation of chiral, aromatic side chains in the peptoid sequence allows for the formation of distinct secondary structures and self‐assembly into supramolecular assemblies, including microspheres. Peptoid microspheres can be coated onto substrates for potential use in biosensor technologies, tissue engineering platforms, and drug‐delivery systems. In order to be useful for these applications, the peptoid coatings must be robust under physiological conditions. In this study, we report the effects of various conditions on the peptoid microsphere coatings, including (i) helicity, (ii) temperature, (iii) pH, and (iv) ionic strength. These studies show that microsphere size decreases with increasing peptoid helicity and the positively charged side chains are positioned on the outside of the microspheres. The peptoid microsphere coatings are robust under physiological conditions but degrade in acidic conditions (pH < 7) and at low ionic strengths (<150 μM).

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly

“…Partially water soluble peptoid foldamers with a pronounced propensity to the formation of helices with three residues per turn were demonstrated to be useful for microsphere coatings, after dissolution in ethanol/water mixtures followed by drying [ 241 , 242 , 243 ]. In particular, the effects of helicity, ionic strength, temperature, and pH in various aqueous solutions were evaluated for peptoids made of the repeating hexameric units, reported in Figure 21 d [ 243 ].…”

“…Partially water soluble peptoid foldamers with a pronounced propensity to the formation of helices with three residues per turn were demonstrated to be useful for microsphere coatings, after dissolution in ethanol/water mixtures followed by drying [ 241 , 242 , 243 ]. In particular, the effects of helicity, ionic strength, temperature, and pH in various aqueous solutions were evaluated for peptoids made of the repeating hexameric units, reported in Figure 21 d [ 243 ]. The secondary structure in solution was determined by CD, while microsphere morphology was analyzed by means of environmental scanning electron microscopy (ESEM) and additional information on stability and surface charge were obtained by differential scanning calorimetry (DSC) and ζ potential measurements by electrophoretic light scattering (ELS).…”

“…In addition, alternating ammonium and p -methoxybenzyl side chains on the third helix face gave a sufficient water solubility and endowed microspheres with a positive ζ potential, therefore favoring the attachment to the negatively charged surfaces of glass substrates. Due to inherently reduced helicity [ 50 , 243 ] and π-stacking ability, as well as excessive water solubility, the hexamer—n = 1 in Figure 21 d—did not form microspheres. On the other hand, longer peptoids gave rise to microspheres whose average diameter decreased as the chain length increased (2.26 μm for the 12 mer, 1.91 μm for the 18 mer, and 1.24 μm for the 24 mer), which was interpreted as the result of a tighter packing, generated in turn by the increase in helicity along the series [ 243 ], even if the exact packing mode was not investigated.…”

“…Due to inherently reduced helicity [ 50 , 243 ] and π-stacking ability, as well as excessive water solubility, the hexamer—n = 1 in Figure 21 d—did not form microspheres. On the other hand, longer peptoids gave rise to microspheres whose average diameter decreased as the chain length increased (2.26 μm for the 12 mer, 1.91 μm for the 18 mer, and 1.24 μm for the 24 mer), which was interpreted as the result of a tighter packing, generated in turn by the increase in helicity along the series [ 243 ], even if the exact packing mode was not investigated. Phase transition temperatures, determined by DSC, were in the range 74–83 °C, and increased with the length, probably due, again, to increased helicity and π-stacking interactions.…”

“…[ 240 ]); ( d ) Example of microsphere-forming peptoids (PMP = p -methoxyphenyl) (Refs. [ 241 , 242 , 243 ]); ( e ) General structure of amphiphilic di-block polypeptoids, with the hydrophilic (blue) and hydrophobic (green) blocks, and vesicle formed (adapted with permission from Ref. [ 244 ]); ( f ) Cryo-EM micrograph of pNeh 26 - b -pNpm 10 vesicles (the arrow indicates the vesicle analyzed in panel ( g )) (adapted with permission from Ref.…”