Polypeptoids

Polypeptoids are a class of peptidomimetic polymers. They are based on an N-substituted glycine backbone. The side chains are attached directly to the polymer backbone via the nitrogen of the amide group rather than at the α-carbon as in polypeptides. As opposed to polypeptides, polypeptoids have an achiral backbone devoid of hydrogen bond donors, which makes them easy to treat while being unable to form secondary structures such as a helix.
The chemical and structural diversity of polypeptoids have enabled access to and adjustment of a variety of physicochemical and biological properties (e.g., solubility, charge characteristics, chain conformation, Hydrophilic-Lipophilic-Balance, thermal processability, degradability, cytotoxicity and immunogenicity).
The structure of polypeptoids combines many of the advantageous properties of bulk polymers with those of synthetically produced proteins. These attributes have made this synthetic polymer platform a potential candidate for various biomedical applications such as encapsulation and biotechnological applications such as biomaterials.
Properties
Chemical and enzymatic stability
The main characteristic of polypeptoids is their high resistance to proteolytic enzymes. The absence of hydrogen on the amide nitrogen prevents proteases and peptidases, which recognise and degrade natural polypeptides, from hydrolysing polypeptoids. The inductive electron-donating effects (+I) provide stability, improving their resistance to proteases and temperature, and enabling them to withstand different biological conditions without undergoing rapid degradation. This means that polypeptoids can be used for medical purposes where a long duration of action is required.
In addition, they have significant resistance to extreme chemical conditions such as pH variations, high temperatures and exposure to certain solvents. They are serve as an alternative to polypeptides, which cannot be used in certain situations where they would be rapidly degrade.
Conformation and structural properties
The difference in structure between a peptoid and an α-peptide lies in the location of the side chain. In a peptide, this chain is located on the amide nitrogen, whereas in an α-peptide it's on the α-carbon.
This difference in structure makes the polypeptide backbone achiral. Because the amide bonds are tertiary, they can undergo isomerization between trans and cis conformations much more easily than the secondary amides of α-peptides.
Wihtout the amide protons, the secondary structure cannot be stabilized by backbone hydrogen bonding in the same way as with peptides. Polypeptoids have higher conformational flexibility than polypeptides. It has been observed that the absence of hydrogen bonds between NH and CO in the main chain prevents secondary structures (notably β-sheets or α-helices) from being formed. Due to their flexibility, polypeptoids are capable of self-assembling into various nanostructures, such as micelles or nanometric polymers that are used to form films and hydrogels. These might be useful properties for applications in materials engineering and medicine.
3. Solubility and biocompatibility
Polypeptoids possess a great flexibility in terms of solubility. By varying the nature of the side chains, multiple bonds could be formed such as water-soluble, amphiphilic or hydrophobic polypeptoids. Due to their high biocompatible and low immunogenic nature, when they are introduced into a living organism, they rarely generate a problematic immune response. This characteristic is necessary for their use in the biomedical field, particularly for medical implants.
Synthesis
1. Solid-phase synthesis method (Zuckermann method)
The Zuckermann method, developed in the liquid phase, consists of a first acylation step using haloacetic acid, followed by a second SN2 step with a primary amine as nucleophile. This allows the synthesis of polymers containing up to 50 units. It produces highly pure compounds (at greater than equal to ninety-five percent) at a low cost and with inexpensive building blocks. TFA is required to cleave the polypeptoids from the resin.
2. Ring-opening polymerization (ROP) of NNCA
The ROP NNCA method (Ring-Opening Polymerization of N-Substituted N-carboxyanhydride) involves opening a N-Substituted N-carboxyanhydride by an amine. It enables the creation of polypeptoids in various forms, whether linear or cyclic.
a) Synthesis of linear polypeptoids
The mechanism begins with an initiation step involving an addition/elimination reaction of a nitrogen- containing group (R can vary including cycle, alkyl chain, etc.) on a carbonyl, followed by a second decarboxylation step. This technique is highly reactive, being susceptible to nucleophilic impurities, which can lead to undesirable polymerization initiations.
b) Synthesis of cyclic polypeptoids (ZROP)
Developed by Zhang and other researchers, this technique uses N-heterocyclic carbenes (NHCs) as nucleophilic initiators. These initiators also act as polymerization mediators by serving as counterions. This mechanism consists of an initiation step, where the NNCA/NCA ring is opened by the NHC, followed by a propagation step, and finally a termination step (termination agents: water, alcohol, etc.). The major advantage of this method is its ability to produce high-molecular-weight cyclic compounds while preventing side reactions through Coulombic attraction between the two chain ends.
Applications
1. Hydrophobically modified polypeptoids HMP
Polypeptoids can be used in the pharmaceutical field, especially in the form of hydrophobic polymer (HMPs). HMPs are hydrophobically modified polypeptoids that contain up to one-hundred monomeric units. The nitrogen atoms are functionalized with alkyl groups, which allows constituting a hydrophobic element, while the rest of the molecule is a highly soluble backbone.
HMPs can thus insert their hydrophobic segments into vesicular lipid bilayers, leading to destabilization of these structures and vesicle rupture, unlike the detergents which will transform the vesicles into mixed micelles of lipids and detergents. At low HMP concentrations, this rupture leads to the creation of large fragments that anchor to intact vesicles, thanks to hydrophobic interactions. At high HMP concentrations, all vesicles rupture into smaller HMP-lipid fragments around 10 nm. These polymer-lipid nano fragments can be used to maintain highly hydrophobic drug species in solution.
2. Use in the Parmaceutical field
In the pharmaceutical field, HMPs are used in the design of new drug delivery systems, through interaction with liposomes, allowing modification of their behavior.
These systems can indeed deliver hydrophilic molecules by encapsulation in the aqueous core of the liposome or hydrophobic drug species by integration into the lipid bilayer. This second alternative is particularly used in cancer treatment.
These HMP molecules are used, for example, to encapsulate in HMP-lipid fragments highly hydrophobic drugs such as SF, a protein tyrosine kinase inhibitor approved by the FDA for the treatment of renal cell carcinoma, thyroid and liver cancer.
3. HMP's example
Research has therefore led to the design of an HMP containing 74% nitrogen functionalized with the neutral N-methoxyethyl group (MeOEt) and 26% functionalized with the N-n-decyl group (C10). This polymer has a molar mass of 13.9 kDa and remains soluble in water, but can perform hydrophobic interactions with liposomes.
These systems thus allow the absorption of SFs into cells, facilitated by the presence of free hydrophobic groups on the HMP, thus allowing their insertion into cell membranes and facilitating endocytic pathways for entry.

Main Menu

See Also

Main Menu