Peptoids and Peptide Based Drugs

Dear Colleagues,

Over the last few decades, peptides have gained increasing interest as attractive drugs due to their unique ability to combine the advantages of antibodies and small molecules and the more favorable specificity and selectivity for their targets. Today, over 80 peptide-based therapeutic agents have been approved by the FDA, and many more are in clinical development. Therapeutic peptides have been identified from various sources, such as living organisms, synthetic chemical libraries, genetic or recombinant libraries, and bioinformatic approaches. They commonly act as hormones, growth factors, neurotransmitters, ion channel ligands, or anti-infective agents, bind to cell surface receptors, and trigger intracellular effects with high affinity and specificity. Recently, the ability of peptides to effectively and selectively inhibit PPIs has also been demonstrated, opening the doors for peptide therapeutics to reach the currently "undruggable" space. Despite these advantages, some peptides still suffer from drawbacks such as poor cellular permeability and high metabolic instability. An attractive alternative that overcomes these challenges is developing peptidomimetics-based therapeutics that are physiologically stable and have high cellular permeability. One class of peptidomimetics, which is an excellent candidate for this purpose, is peptoids, N-substituted glycine oligomers. Peptoids can be synthesized on solid support from primary amines, allowing to introduce a variety of functional groups within their sequence. They can fold into well-defined secondary structures in solution and could be employed in various biological activities, including protein–protein interactions and selective extraction of metal ions. Importantly, peptoids, which cannot form hydrogen bonding because they comprise a tertiary amide backbone, display a significantly improved stability profile in vivo, are more lipophilic than peptides, and have some intriguing pharmacological properties: they are stable against proteases and peptidases, are tolerant towards high salt concentration and various pH conditions, and have better bioavailability and better cell permeability than peptides. Due to these advantages, peptoids are becoming attractive candidates for therapeutic and diagnostic applications. To date, peptoids have demonstrated bioactivity as protein mimics and as replacements for small molecule drugs. Recent advances in research on peptoid as therapeutics in the last several years include in vitro and in vivo studies in the fields of lung surfactant therapy, antimicrobial agents, diagnostics, and anticancer agents and inhibitors. Some of these peptoids are designed de novo, while others are prepared by converting interesting peptides into peptoids. The latter, however, is associated with a reduction in the biological activity related to even minor structural changes, and the development of peptide–peptoid chimeras (peptomers) can help in creating better peptoid-based therapeutics.

Dr. Laura Zaccaro
Dr. Annarita Del Gatto
Dr. Galia Maayan
Topic Editors