Halogenation as a tool to tune antimicrobial activity of peptoids

Abstract

Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N-substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity.

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

“…For example, while MXB-9 exhibits potent antiviral activity, its structural analog MXB-10 has no effects on viral propagation. This difference in activity potentially can be explained by differences in net molecular hydrophobicity upon halogen substitution as previously reported by Molchanova et al [34]. In this study they found an increasing antimicrobial activity correlating with increasing hydrophobicity, until a threshold was reached where the activity dropped.…”

“…Given the partial success of MXB-1 and MXB-5, a further library of compounds was developed by hybridizing the key features of these compounds. The activity and potency of these cationic, amphipathic peptoids was found to be affected by their self-assembly into stable, ellipsoidal micelles or other structures (unpublished results; and [ 34 ]).…”

“…The other contribution to this library came in the form of halogenated peptoids, which were first developed and explored by Molchanova et al [ 34 ]. They synthesized a library of 36 halogenated analogs of MXB-1.…”

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

“…Some fluorine substituted peptoids had enhanced antimicrobial activity against both Gram-(+) and Gram-(-) bacteria without toxicity to mammalian cells [ 216 ]. Recently, a study on the effect of the halogenation in α-peptoids investigated the relationship between the nature of the halogen and the degree of halogenation, their ability to self-assemble into nanostructures and their antimicrobial activity [ 217 ]. Sets of scaffolds of four sizes were used containing alternating NLys and NPhe units, where F, Cl, Br and I atoms were introduced into position 4 of the phenyl rings.…”

Bio-instructive materials on-demand – combinatorial chemistry of peptoids, foldamers, and beyond

“…255 Furthermore, the group was able to establish a correlation between the biological effect of the halogenation and the relative hydrophobicity of the compounds, as well as their self-assembly properties. 256 The lipophilicity of peptoid oligomers greatly affects antimicrobial activity. By screening a peptoid library against several bacterial strains using a peptoid library agar diffusion (PLAD) assay, Turkett and Bicker established a basis for future designs of peptoid libraries.…”