Peptoids are small sequences of the amino acid glycine modified on the nitrogen atom. They look like amino acids but the ramification is located on the nitrogen rather than the alpha-carbon. Plus, as the amino acid glycine, they also lack chirality. The concept of peptoids was first introduced in the 80s.  Back at the time, important biological targets such as enzymes, growth factors and antibodies were quickly identified, produced and validated due to new discoveries of gene editing. However, small organic molecules to screen against those biological targets weren’t made at the same pace.
So, a small start-up company called Protos Corp. in Emeryville, CA decided to venture in the field of drug discovery providing libraries of compounds as chemistry service. The team of scientists led by Dr. Dan Santi immediately focused on a biomimetic approach and aimed at developing nature-like systems to address the problem of binding. They realised that, at a biological level, we have a small number of biomolecules such as nucleic acids and peptides which can be arranged in myriads of sequences to detect a promiscuous variety of molecules.
However, when it comes to design potential drugs, we have to consider how these substances interact and transform inside living organisms, an area of science called pharmacokinetic. Peptides and nucleic acids have poor pharmacokinetic properties which means, they break down into their individual constituents quite quickly when given to living organisms. Therefore, the team of scientists at Protos corp. came up with the idea of making analogous of peptides and called these new structures peptoids. Differently from peptides, peptoids have the ramification on the nitrogen instead of the alpha carbon (see figure) and were designed to be less susceptible to the action and proteases. In fact, these enzymes, which break down peptides into amminoacids, are the biggest factor preventing the use of peptides as drug candidates.
Speculations were made on the use of peptoids as biologically active molecules. Peptoids did have longer survival rates when given to living organisms and were also easy to make in the chemistry lab. Additionally, the lack of free nitrogen made these motives more hydrophobic, though this could have been a problem in terms of binding due to the lack of formation of hydrogen bonds. The lack of chirality seemed also a potential problem, though the more flexibility and higher number of conformations could have been beneficial in binding a diverse variety of targets.
Extensive studies were made to understand the properties of these new substances.  Peptoids demonstrated antibacterial activity [3, 4] for example, and libraries of peptoids have been used to elucidated aspects of Alzheimer disease and multiple sclerosis [5, 6]. In one study , a team of scientists at Novartis tested a peptoid as a biomarker for the Alzheimer disease and found that this fragment could be used as a diagnostic tool. In another study, the authors screened libraries of peptoids against biological targets (in this specific case they used antibodies) and found diagnostic markers for multiple sclerosis in mouse models.  Additionally, a few peptoids in these libraries of compounds were successfully identified as biomarkers for Alzheimer disease in humans .
In a recent publication in Green Chemistry, the authors proposed a new and more sustainable approach for the synthesis of peptoids.  Instead of using traditional solvents such as dichloromethane, dimethylformamide and tetrahydrofuran , they successfully tested water-based systems as solvent for the chemical synthesis of peptoids. Specifically, they used micellar water systems as solvents and carried out the formation of the unnatural peptides in the nitrogen to carbon direction. Notably, the intermediates of each steps could be purified only by extraction. The two surfactants used to create the micellar solutions were arguably defined as environmentally benign and both are commercially available.
This method was applied to the synthesis of analogues of biologically relevant structures such as an antimicrobial and an opioid neurotransmitter. To highlight the more sustainable outlook of the procedure, the author compared the E-factor, a green chemistry metric, of the synthesis of the analogue of the opioid neurotransmitter of this method with one previously reporter using solid phase synthesis.  The E-factor was estimated to be 4 times lower if water was included and 17 times lower if water was not included in calculating the green chemistry metric.
The unique features of peptoids such as resistance to enzymatic degradation made them attractive materials for long-term implantation or use in regenerative medicine. They have also demonstrated promising results as biomaterials and in tissue engineering applications. In fact, they can self-assemble into well-defined nanostructures, making them useful for creating scaffolds that support cell growth and tissue regeneration. 
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 Biopolymers, 2011, 96, 545
 Expert Opin. Drug Discovery, 2015, 10, 1163
 Proc. Natl. Acad. Sci USA, 2008, 105, 2794
 Org. Biomol. Chem. 2006, 4, 1441
 PLoS One 2010; 5, e15725
 Cell, 2011, 144, 132
 Green Chem., 2023, 25, 3615
 Chem. – Eur. J., 1998, 4, 1570
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