Structure–function relationships in peptoids: Recent advances toward deciphering the structural requirements for biological function

Abstract

Oligomers of N-substituted glycine, or peptoids, are versatile tools to probe biological processes and hold promise as therapeutic agents. An underlying theme in the majority of recent peptoid research is the connection between peptoid function and peptoid structure. For certain applications, well-folded peptoids are essential for activity, while unstructured peptoids appear to suffice, or even are superior, for other applications. Currently, these structure-function connections are largely made after the design, synthesis, and characterization process. However, as guidelines for peptoid folding are elucidated and the known biological activities are expanded, we anticipate these connections will provide a pathway toward the de novo design of functional peptoids. In this perspective, we review several of the peptoid structure-function relationships that have been delineated over the past five years.

Peptoids for biomaterials science

“…In addition, peptoid libraries hold significant promise for biomaterials discovery. The knowledge gained from two decades of peptoid peptidomimetics research 10,13,[24][25][26]56 could potentially be quickly translated for biomaterials applications. Design rules for dialing in secondary structure and peptoid folding by sidechain design and sequence control have emerged.…”

“…Design rules for dialing in secondary structure and peptoid folding by sidechain design and sequence control have emerged. 10,13,15 A catalogue of bioactive peptoids has been included in a recent review. 17 Peptoids have also been shown to exhibit enhanced cell penetration compared to the corresponding peptide sequences, 57 but they can also be tuned, as in the case of some antimicrobial peptoids, to target bacterial membranes.…”

“…8,13 These include antimicrobial peptoidsÑa significant area of peptoid research discussed in recent reviews. 10,25,27 Recent studies have also demonstrated peptoid sequences potentially useful in diagnosing or treating amyloid diseases.…”

“…21,22 The biorecognition abilities of peptoids have been demonstrated through two decades of peptoid therapeutics research, protein-binding sequence discovery, and secondary structure design, which have been recently reviewed elsewhere. 10,15,[24][25][26][27] As originally envisioned, 7 many bioactive sequences have been discovered by screening peptoid libraries. 8,13 These include antimicrobial peptoidsÑa significant area of peptoid research discussed in recent reviews.…”

“…[10][11][12][13][14] Chirality and control over secondary and higher order structure formation can be reintroduced by sidechain chemistry and sequence designs. 10,12,13,15 Synthetic convenience and modularity in generating sequences with monomer-level programmability over sidechain chemistry and chain length derive largely from the introduction of the submonomer solid phase synthesis by Zuckermann et al (Figure 1B). 7,16 No backbone protection is required and diverse primary amines, many of which are commercially available, can be incorporated as sidechains in an iterative protocol.…”