Peptides and Their Many Uses

A study published in Molecules investigated a review of peptides, studying their history, function, and its potential use in biomedicine.¹ 

Peptides consist of at least 2 amino acids and can be either an oligopeptide—a short chain of amino acids—or a polypeptide—a long chain of amino acids and they a unique class of biomolecules and have filled the therapeutic niche because of their specific biochemical and therapeutic features.  

Short Peptides

There are structural modifications to overcome these limitations and can improve the physicochemical properties, such as greater stability. There is the option of double-bridged peptides, and it reduces the peptide backbone flexibility and causes limited availability for enzymes. The conjugation to cell-penetration peptides can lead to better drug bioavailability and therapeutic efficiency, potentially leading to new treatments. 

There have been efforts made to develop short peptides or peptidomimetics to have pharmacological properties. Structural changes can happen by selectively substituting along the sequence specific residues with other residues or by substituting certain residues of the sequence with non-coded α-amino acid residues.

Cyclic peptides are already used in the treatment of diseases such as insulin, penicillin, cyclosporin, and gramicidin S and these peptides versus linear peptides have increased chemical and enzymatic stability, receptor selectively, and improved pharmacodynamic properties. 

The engineering of stable peptide moieties, which are the cyclic counterparts and non-peptide mimetics is important. Structure-activity studies have showed the importance of 3 aromatic amino acids TYR, HIS, PHE, and the C-terminal carboxylate for activity. This discovery, combined with Nuclear Magnetic Resonance techniques, the authors designed synthesized angiotensin II receptor blockers by rotation of the alkyl chain on the imidazole ring

This is important as the perspective use of angiotensin receptor blockers (ABM) as they were recently found to protect hypertensive patients from Covid-19.

The very short peptides are easier and less expensive to synthesis, higher mechanical stability, good tissue penetration, and less immunogenicity. They do have better structural optimization. Ultra-short peptides are also better for oral treatments and overcome many of the issues that long peptides run into while also providing potential for cancer cell growth inhibition.

The simplest cyclo-peptide (2,5-diktopiperazine [DKP], piperazine-2,5-diones, 2,5-dioxopiperazines, and dipeptide anhydrides) have inter alia superior rigidity, 3-dimensionality, higher cell permeability, and diverse bioactivities like anticancer, antiviral, and antioxidant. They also prevent neurodegeneration, quorum sensing, cell to cell signaling, as drug delivery systems. They were found in the central nervous system, gastrointestinal tract, and blood.

Synthesis

When performing solution peptide synthesis, each step requires product purification by using a gel chromatography or crystallization, whereas in solid-phase synthesis (SPPS) requires only a simple washing of the peptide and because of this, researchers can design peptide synthesizers and automate the procedure. 

This synthesis is necessary to separate the amino acids from the peptide and solution phase synthesis can be used to modify the amino acids or amide bonds. Cyclization can also be used to synthesize these peptides also. 

Though there are many peptides are synthesized by SPPS, some can be difficult to do, and these are called “difficult sequence-containing peptides.”

“During the chain elongation, intra-/inter-molecular hydrophobic interactions and/or hydrogen bondings cause aggregation of protected peptides on the resin to induce incomplete coupling and deprotection. Furthermore, after final deprotection, hydrophobic peptides hamper HPLC purifications using H2O-MeCN system,” wrote study authors.

The O-acyl isopeptide method was developed to counter these issues and it is used by synthesizing the in a form of an O-acyl isopeptide, which contains an O-acyl isopeptide bond instead of the native N-acyl peptide bond at a hydroxy group-containing amino acid residue. The peptides synthesized this way include Alzheimer’s disease-related amyloid β peptide 1-42 (Aβ42, amylin, vaccine peptide, insulin derivatives, and collagen peptide.

In Silico Studies

Molecular dynamics (MD) simulations are a useful tool for prediction and/or reproduction of experimental 3D structures of small proteins. The interactions of peptides are needed to be understood to progress on both modeling and thermodynamic aspects of their interactions and the understanding of the content of cells coming from the peptide in synthetic and protein degradation aspects. This matters in the future use of the peptide. 

MD has 2 scales, atomistic and coarse grain (CG), where is main difference is the way the atoms of a peptide are displayed. The atomistic scale shows all the atoms and CG scale shows the atoms in grouped beads. Both are used to look at the interaction of the peptide with the lipid membrane. 

The partition and insertion of single peptides in membrane of different composition have been broadly investigated using unbiased MD simulations in both scales. This has helped identify specific interactions, peptide conformation, and bilayers properties.

Other information can be found by calculating the peptide reaction path. Several methods have been used like the umbrella sampling, adaptive biasing force (ABF) method, the Wang-Landau algorithm, steer molecular dynamics, and metadynamics. Also, to take a closer look at the cooperative effects of peptides, like pore formation, has led to better therapies. 

Peptide Based Therapies

Peptides are researched for many different uses like molecular transporters, gene delivery, vaccines, neurodegenerative therapy, treatment for autoimmune diseases, stem cell research, and anti-viral for Covid-19. For more details on these developments, please read the article.

Nutraceuticals have use plant proteins which have diverse peptides to help add benefits for patients. Peptides with 2 or 3 amino acids pass easily into the blood after digestion and they have positive effects on blood pressure and lipid metabolism, along with analgesic, anti-thrombosis, anti-atherosclerotic and opioid agents.

Marine bioactive peptides have many advantages like anti-inflammatory, anticancer, and antioxidant activities and whether derived from non-edible marine organisms or seafood processing by-products, may have potential applications in the discovery of peptide-based therapeutic agents and formulation of nutraceuticals.¹

Peptide-based cosmeceuticals acting against both intrinsic and extrinsic aging and improving the health and appearance of skin are becoming increasingly popular, according to study authors. This heightened popularity is because of the collagen stimulation, wound healing, wrinkle smoothing, combined with the antioxidative, antimicrobial, and whitening effects. Natural peptides offer a more sustainable way to create these colismeceuticals also as they are highly biodegradability, low toxicity, manufacturing cost, and availability to scale up production.

“To sum up, short peptides can be a secret of idealized smart therapies,” wrote study authors.

Disclosure:

The authors declare no conflict of interest.

Reference:

1. Apostolopoulos V, Bojarska J, Chai T-T, et al. A global review on short peptides: frontiers and perspectives. Molecules. 2021;26(2):430. doi:10.3390/molecules26020430