Foldamers are artificial self-organizing molecules. They can form higher order structures and show cooperatively and heterogeneity in sequences.
Types of foldamers
Foldamers may be peptoids, aromatic and aliphatic oligoamides. Peptoides are N-substituted polyglycines were the side chains are present on a nitrogen atom. They have less structural complexity which makes them easier to engineer or design.
Aromatic oligoamides have aromatic or heteroaromatic rings linked by amide bonds, and they form helical three-dimensional structures. Aliphatic oligoamides can generate α, β, γ, or δ peptides based on the position of the amide group which forms.
Key features of alpha foldamers
Unlike other peptidesm, alpha peptide foldamers can be synthesized artificially and do not require bacterial fermentation.
The key features of alpha foldamers are the following: they can form a stable secondary structures and have a large molecular surface. They orientation of the side-chain groups is important as it inhibits movement, creating a structure with low conformational freedom which binds tightly the molecules it interacts with. In addition, it provides stability and protects against proteolytic degradation.
Applications of alpha foldamers
The search for new molecules with antibacterial properties is an area for ongoing research with the rise of antibiotic resistant diseases. Antimicrobial peptides act by disrupting the integrity of bacterial membranes and thus, killing the bacteria.
These peptides are helical and amphipathic (characterized by polar and non-polar side-chains on the surface of the helix). When this structure integrates in to the bacterial membrane, it can create pores or channels on the membrane leading to leaking of intracellular contents. Till date, there has been no reported antibiotic resistance towards these α peptide foldamers which is a significant result.
Cell penetrating foldamers
Certain peptide foldamers can penetrate the cell membrane and thus, can be used to deliver chemotherapeutics, proteins and small molecules. Although it is not clear as to how the foldamers are uptaken by the cell, different peptide foldamers may have different permeability properties. Alpha peptide foldamers have been used to deliver siRNA which leads to down regulation of the targeted genes.
Autophagy is a process where unnecessary cell parts are degraded. Certain peptide foldamers can penetrate inside the cell membrane and increase the rate of autophagy which can cause disease conditions.
Modifying protein-protein interactions
Protein-protein interactions govern several biological processes and have potential medicinal and pharmacological applications. The interaction of proteins with proteins involves large surface areas and cannot be altered using small molecules.
Several diseases, such as chronic inflammation and cancer involve altered protein-protein interactions. In such cases, structure dependent alpha peptide foldamers have found to modify protein-protein interactions which can further lead to pharmacological applications.
Traditional peptides undergo fast proteolytic degradation and have shorter half-lives. They also have reduced ability to cross cell membranes. Alpha/beta foldamers are 100-times more resistant to proteolytic degradation and thus superior to conventional peptides for various applications.