https://orcid.org/0000-0002-9354-6592
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ABSTRACT
Introduction
Peptide foldamers play a critical role in pharmaceutical research and biomedical applications. This review highlights recent (post-2020) advancements in novel foldamers, synthetic techniques, and their applications in pharmaceutical research.
Areas covered
The authors summarize the structures and applications of peptide foldamers such as α, β, γ-peptides, hydrocarbon-stapled peptides, urea-type foldamers, sulfonic-γ-amino acid foldamers, aromatic foldamers, and peptoids, which tackle the challenges of traditional peptide drugs. Regarding antimicrobial use, foldamers have shown progress in their potential against drug-resistant bacteria. In drug development, peptide foldamers have been used as drug delivery systems (DDS) and protein-protein interaction (PPI) inhibitors.
Expert opinion
These structures exhibit resistance to enzymatic degradation, are promising for therapeutic delivery, and disrupt crucial PPIs associated with diseases such as cancer with specificity, versatility, and stability, which are useful therapeutic properties. However, the complexity and cost of their synthesis, along with the necessity for thorough safety and efficacy assessments, necessitate extensive research and cross-sector collaboration. Advances in synthesis methods, computational modeling, and targeted delivery systems are essential for fully realizing the therapeutic potential of foldamers and integrating them into mainstream medical treatments.
Article highlights
Foldamers designed with oligomer units are engineered to form specific secondary structures that exhibit chemical properties distinct from those of natural peptides.
Peptidomimetics can enhance enzymatic stability through variations in the amino acid composition, secondary structural alterations, and increased lipophilicity.
Innovative structures of foldamers have demonstrated efficacy against drug-resistant bacteria, highlighting their potential as next-generation antimicrobial agents and adjuvants.
The structural and functional diversity of foldamers present promising applications in drug delivery systems, enabling targeted therapy and potentially mitigating the side effects associated with conventional therapeutics.
Foldamers, with their structural flexibility and versatility, offer promising potential as inhibitors of protein-protein interactions (PPIs), as they can be designed to match the target sites of these interactions.
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Abbreviations
| CPPs | = | cell-penetrating peptides |
| PPIs | = | protein-protein interactions |
| DDS | = | drug delivery system |
| dAAs | = | α,α-disubstituted α-amino acids |
| α-AA | = | α-amino acid |
| β-AA | = | β-amino acid |
| γ-AA | = | γ-amino acid |
| Aib | = | α-aminoisobutyric acid |
| trans-ACPC | = | trans-2-aminocyclopentanecarboxylic acid |
| sulfono-γ-AAs | = | sulfono-γ-amino acids |
| AMPs | = | antimicrobial peptides |
| Orn | = | ornithine |
| Dab | = | (2S)-2,4-diaminobutanoic acid |
| Arg | = | arginine |
| His | = | histidine |
| Api | = | 4-aminopiperidine-4-carboxylic acid |
| β3,3-Pip | = | 2-(4-aminopiperidin-4-yl)acetic acid |
| β2,2-Ac6c | = | 1-(aminomethyl)-cyclohexane-1-carboxylic acid |
| MIC | = | minimum inhibitory concentration |
| PDAP | = | poly(DL-diaminopropionic acid) |
| ATCs | = | 4-amino(methyl)-1,3-thiazole-5-carboxylic acids |
| Mag2 | = | magainin 2 |
| MRSA | = | methicillin-resistant staphylococcus aureus |
| LPSs | = | lipopolysaccharides |
| SAR | = | structure-activity relationship |
| InsP6 | = | myo-inositol-1,2,3,4,5,6-hexakisphosphate |
| mRNA | = | messenger RNA |
| siRNA | = | small interfering RNA |
| pDNA | = | plasmid DNA |
| CF | = | 5(6)-carboxyfluorescein |
| MD | = | molecular dynamics |
| APC | = | cyclic β-amino acid |
| d-azp | = | D-aza proline |
| PDL1 | = | programmed death ligand 1 |
| PCVs | = | polyelectrolyte complex vesicles |
| PNAG-COOH | = | 3-mercaptoacetic acid |
| VEGF | = | vascular endothelial growth factor |
| TNFα | = | tumor necrosis factor-α |
| VDR | = | vitamin D receptor |
| MDM2 | = | mouse double minute 2 homolog |
| DAXX | = | death domain associated protein 6 |
| CD14 | = | cluster of differentiation 14 |
| COPD | = | chronic obstructive pulmonary disease |
| PARP | = | poly(ADP-ribose) polymerase |
| E1 | = | ubiquitin-activating enzymes |
| E2 | = | ubiquitin-conjugating enzymes |
| UBA1 | = | ubiquitin activating enzyme 1 |
| HIF-1α | = | hypoxia-inducible factor 1α |
| αS | = | α-synuclein |
| PD | = | Parkinson’s disease |