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Approaches Used To Overcome the Top Drawbacks of Peptide Drugs

Drug delivery to patient neoplasm is an area that has experienced major challenges, and it still possesses ongoing clinical challenges. Nearly five decades ago, the research world saw the proposal of function-blocking monoclonal antibodies, as a therapy for cancer. However, these particles had large molecular sizes that made their commercial development for anti-body fragment therapies, a huge challenge. However, with improvements and advancements in technologies, they were later approved for commercialized cancer therapeutics and diagnostics, two decades later.

During this period, a classic development to be witnessed was the discovery of a radiolabeled peptide analog of somatostatin. This was applied in the targeting of neuroendocrine tumors that are usually expressed as SST receptors, instead of going for the receptor as an antibody. Due to the ability to use peptides as a targeting moiety in the diagnosis and treatment of cancer, it has made possible the development of peptide drugs, both in the pharma and academic fields. Also, other than cancer treatments, peptides with the ability to copy natural peptide hormones may be applicable in instances where therapeutic opportunities are needed. For example, synthetic human insulin has been used due to its clinical efficacy, in managing patients suffering from conditions such as diabetes.

When compared to small molecules such as proteins, it is evident that peptides are a completely unique group of pharmaceutical compounds. This is primarily because of their unique therapeutic and biochemical properties. Also, apart from peptide-based natural hormones, peptides have long been viewed as suitable drug candidates, with unique capabilities to disrupt protein-protein interaction, and effectively target intracellular molecules, like tyrosine kinases. Protein-protein interaction is usually seen as the base of all cellular processes.

Most of the biochemical processes usually feature activated receptors, with the ability to directly or indirectly regulate a variety of enzymatic processes, including the transcription of nucleic acids. Compounds designed with the ability to specifically bind to these receptors, can usually work as agonists or antagonists, with a variety of downstream consequences on how the interacting cells behave. Small molecules and peptides with the ability to interfere with how protein-protein interaction work, are, therefore in great demand, since they are being viewed as viable therapeutic agents in the pharma industry. This is because they have great potential for modulating disease-associated protein interactions.

Sadly, it is a humongous challenge for both protein biochemists, and biologists, to understand just how the molecular recognition mechanism, as well as the delineation binding activity of the protein-protein interaction, works. The major reason behind this, is because the smaller particles have a better ability to bind in the deep folding pockets of proteins, compared to the proteins with larger molecules. In as much as monoclonal antibodies are seen to be more effective in the recognition of PPI interfaces, it is not possible for them to penetrate the cell membranes, so that they are able to reach and reorganize their intracellular targets.

The intrinsic challenge of peptide compounds

Peptide compounds that have been synthetically manufactured, don’t play as much role in regulating normal physiology, compared to natural polypeptides, like growth factors, hormones, and neurotransmitters. With peptide compounds, there are always two major challenges faced – difficulty when it comes to membrane permeability, and instability in vivo. It is also a fact that due to proteolytic degradation, peptide compounds tend to have a shorter half-life, and it also impacts the bioavailability of the compounds. To achieve clinical effective concentration, it may be necessary to ensure routine dosing of the compounds. There are various modifications that have been done chemically, to prevent or slow down proteolytic degradation, as well as improving the in vivo half-life of the peptide compounds. Below is a brief guide on how modern technologies are being used to make peptides less susceptible to the processes of proteolytic degradation, so that the full power of peptide compounds can be realized.

Termini Protection

It is possible for the process of proteolysis to take place at both the C-termini and N-termini of a peptide. It is possible for this to happen for up to 500 peptidases and proteases, and this includes carboxypeptidases and aminopeptidases. There is enough evidence that various amino acid residues at C- or N- termini, can lead to varying degrees of proteolysis and degradation. This means that if it was possible to modify the C- or N- termini sequence while maintaining the ideal targeting specificity and affinity, then it may be possible to reduce the effects of proteolytic degradation, while at the same time improving the bioavailability of the compounds. Also, if those modifications can allow for the proper functioning of the compound, then it means that C-terminal amidation or N-terminal acetylation, may make it possible to increase in-vivo stability.

Drawbacks of Peptide Drugs

Identification of critical residues with non-chemical methods

For many biologists, the preferred method of chemical modification usually depends on the biologist’s knowledge and expertise, in chemistry, as well as collaboration. However, there are certain methods that could be easily used, as they are still essential for biological study, regarding peptide design. To begin with, the identification of the minimum amino acid residue is vital for peptide activity. Generally, this can be realized through the repetitive truncation of the amino acids from the N- or C- terminals of a leader sequence. This leads to the determination of the core peptide motif, which would be necessary for biological activities. Secondly, a process known as alanine screening may be applied when determining the contributing amino acids to the biological activity of the peptide.

When screening is done to the biological functionality of a library of peptides, especially in cases where the amino acids have been substituted by alanine, it becomes relatively easy to identify the critical amino acids. The reason for using alanine for the substitution, is simply because of its small size, and because it is uncharged, it will not interfere with any of the functions of the nearby side chains. In the recent past, there are more complex scanning techniques being deployed, and additional physical properties, such as basicity, acidity, and hydrophobicity are being considered. However, these scanning techniques still need the validation of molecular biologists, before they can be used for the mature development of improved biological activities.

Substitution of synthetic amino acid and backbone substitution

It is possible for the amino acid scanning discussed, to provide incredibly useful information, which can be applied to the design of further modification. This is especially the case when you are considering a side chain group of a given amino acid residue. For example, synthetic enantiomer amino acids are thought to enhance resistance to protease, because of the fact that they are stereo-chemically reversed, and as such, they are not usually recognized as protease substrates. One good example of this, is Arginine. It is possible to effectively replace this with beta-3 analogs, as well as other variants like ornithine or lysine. It is known that most of the natural amino acids have a few close analogs, which may be effective for substitution on the critical residue, so as to enhance the rigidity, as well as the confirmation of the peptide. There are also unnatural analogs that may be used for aromatic amino acids to replace the beta-methyl group. In recent pre-clinical studies, a side chain modification of a monomeric helical peptide was conducted, whereby it was used as a tritagonist for activating the GLP-1, and glucagon receptors. In studies involving rodents with obesity, the use of this tritagonist peptide showed a significant reduction in body weight, as well as a reduction in diabetic complications, without any signs for cross-reactivity, at non-specific receptors.

Membrane Protein-Facilitated Intracellular Peptide Uptake

Of all the groups of transmembrane receptors, the G-protein coupled receptors, are usually viewed as a superfamily, because of their ability to transport a wide range of molecules across the cell membranes. In as much as peptides may sometimes act as natural ligands for GPCRs, just a small group of extracellular peptides have the ability to actively go through the plasma membranes. These sets of peptides that portray the ability to move across the cell membranes are now being referred to as cell-penetrating peptides – CPPs. In most cases, CPPs have been observed to be highly hydrophobic, and comprise between five and 30 amino acid long peptides.

The structural and the molecular mechanisms used by the cell-penetrating peptides that allow them to effectively carry out intracellular delivery, are yet to be understood fully, and, currently, there are lots of studies concerning how the CPPs can be used in the development of peptide compounds that will have the ability to be smoothly delivered, across the cell membranes, while at the same time, improving their oral bioavailability. The development of most of the biotherapeutic peptides, has so far been anchored in the CPP’s ability to successfully traverse the membrane lipid bilayer. Also, the highly cationic and amphipathic nature of antimicrobial peptides, has made it possible for them to successfully move through the cell membranes, to effectively remove microbes, as well as infectives, through the modulation of immune responses.


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