Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals

Abstract

Peptoids are a developing class of peptide-like oligomers originally invented for drug discovery in the early 1990s. While peptides hold great promise for therapeutic applications, current development of peptide-based pharmaceuticals is hindered by their potential for misfolding and aggregation, and particularly, for rapid in vivo degradation post-administration. Researchers have investigated alternative peptide-like constructs that may be able to circumvent such complications. Peptoids comprise a peptide-based backbone and N-substituted glycines for side chain residues, resulting in complete protease-resistance. Synthesis of peptoid sequences up to 50 units in length allows for controlled sequence composition and incorporation of diverse side chain chemistries. Though the landscape of peptoid structure is not clearly defined, secondary, tertiary, loop, turn, and random structures have been identified. As protease-resistant isomers of peptides, peptoids are being developed as versatile molecular tools in biochemistry and biophysics, and are becoming attractive candidates for therapeutic and diagnostic applications. Peptoids have thus far demonstrated bioactivity as protein mimics and as replacements for small molecule drugs. In this review, we discuss the most recent advances in peptoid research on the therapeutic front in the last few years, including in vitro and in vivo studies in the fields of lung surfactant therapy, antimicrobial agents, diagnostics, and cancer. We particularly focus on the biophysical activity of lipid-associated peptoids and their potential therapeutic applications.

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.…”

“…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.…”

“…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.…”

Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23

“…Thus, peptide drug design strategies often seek to engineer structure into the peptide [5]. These approaches include induction of secondary structure such as β-turns, α-helices and β-hairpins [6]; head-to-tail cyclization [7, 8]; and incorporation of non-standard amino acid residues, as in peptoids [9]. Of particular interest is creating a peptide fold through formation of disulfide bonds between cysteine residues that are distant from each other in the peptide sequence.…”

N-Substituted Arylsulfonamides as Alternative Building Blocks in Peptoid and Peptide Synthesis

“…Peptoids (oligo N-substituted glycines) are peptidomimetic oligomers showing attractive structural and pharmacological properties for the development of therapeutic candidates and molecular tools [1,2]. Compared to peptides, peptoids are resistant to proteases and show improved cell permeability [3,4].…”