β-Peptoid Foldamers at Last

Abstract

For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

Poly(2‐Oxazoline)‐Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance

“…Hence, peptide mimetics have attracted a great deal of interest for functional studies, mechanistic investigations, and variable applications . Currently, only very limited classes of chemical structures are available to explore functional mimics of peptides, such as peptoids (obtained from the N‐substitution strategy) and β‐peptides (obtained from the backbone extension strategy; Figure a) . Therefore, there is a need to develop new classes of functional mimics of peptides.…”

Polypeptoids synthesis based on Ugi reaction: Advances and perspectives

“…Nevertheless, an inherent weakness associated with peptides (Figure ) is their instability toward proteases, which severely diminishes their bioavailability. This intrinsic obstacle has been circumvented by the design of novel peptidomimetics, that is, β‐peptides or peptoids (Figure ) . Peptide‐peptoid hybrids are an interesting kind of peptidomimetics, and such hybrid polymers can benefit from both classes of compounds .…”

“…Therefore, because of the possibility to build new libraries of polypeptoids, the Ugi reaction has recently provided a novel platform in polypeptoid chemistry. Solid‐phase synthesis and NNCA approach toward polypeptoids have already been widely documented and represent the most important work realized so far . Less documented efforts have also been made in Ugi processes to avoid tedious procedures and strict synthetic conditions trapped in the solid‐phase synthesis and NNCA polymerization, as these are troublesome for large‐scale preparation.…”

Oligomers of α‐ABpeptoid/β3‐peptide hybrid

“…These desirable features may allow them to serve as an important tool in various biological applications. Indeed, a myriad of peptidomimetic foldamers have been developed including β‐ and γ‐peptides, oligoureas, oligopyrrolidines, γ‐AApeptides, α‐aminoxy acids, azapeptides, oligotriazoles, aromatic oligoamides, and peptoids …”