Therapeutic peptides refer to a special class of pharmaceutical agents that features a series of well-organized amino acids. Research revolving around therapeutic peptides begins with fundamental studies about human hormones, including insulin, gonadotropin-releasing hormone, vasopressin, and oxytocin, including their respective physiological activities in the human body.
The very first synthesis of the therapeutic peptide was insulin in 1921, and since then, there have been incredible advancements with the therapeutics, leading to the approval of more than 80 peptide drugs that are currently being used to treat a variety of ailments across the globe. Consequently, the development of peptide drugs from therapeutic peptides has become one of the hottest topics in the pharmaceutical research arena over the past few years.
During the first half of the 20th century, there was the discovery of a variety of life-saving bioactive peptides such as insulin, which was initially studied and isolated from natural sources. The discovery and development of insulin, which is nothing but a peptide with 51 amino acids, was one of the biggest scientific achievements of the century. Insulin was first isolated in 1921, and by 1923, it became a commercial peptide drug.
Since then, it has been life-saving to millions of diabetes patients in several countries across the globe. However, the high market demand for insulin in the 20th century could not be sustained with the production of human insulin. This caused animal-derived insulin to dominate the market for nearly a century until it was replaced by recombinant insulin.
Over the years, more peptide hormones and their therapeutic receptors have been discovered. Current technologies used for protein purification and synthesis have led to phenomenal progress, hence speeding the development of peptide drugs, making it possible for the approval of more than 40 peptide drugs. It is also important to note that synthetic peptides have also begun to be developed alongside natural peptides.
The development of peptide drugs entered a new era with the advent of the 21st century. This was made possible with the advancements in structural biology, new synthetic and analytic technologies, and recombinant biologics which greatly helped to accelerate the drug development processes. Ever since, there has been a sophisticated system of peptide drug development in place.
This fairly advanced and sophisticated system includes drug discovery and drug design, the synthesis of the peptides, structural modification of the peptides, and the evaluation of the peptides' activities. Presently, it is estimated that about 33 non-insulin peptide drugs have been approved worldwide since 2000. Additionally, these peptide drugs are advanced in design and formulation since they are not just mere hormone mimics or made only from natural amino acids.
Peptide drugs currently account for a huge portion of the pharmaceutical market, with sales topping over $70 billion in 2019. This accounts for more than double the figures that were recorded back in 2013. According to research done by Njardarson et al., the top 200 sales of drugs for the year 2019 includedabout 10 non-insulin peptide drugs. Noteworthy is the fact that the top three sales of peptide drugs were all GLP-1 analogs designed for treating Type 2 Diabetes.
Advantages and Drawbacks of Therapeutic Peptides
Generally, therapeutic peptides tend to act as growth factors, hormones, ion channel ligands, anti-infective agents, or neurotransmitters. They have the ability to bind themselves to the cell surface receptors and trigger certain intracellular events with high affinity and specificity. Their mode of operation is usually similar to the action of biologics, including those of therapeutic proteins and antibodies. But when you compare their actions with the actions of biologics, you will observe that therapeutic peptides have less immunogenicity and their production cost is also relatively lower.
Most of the small molecule drugs tend to have an extended therapeutic history with certain inherent advantages, which also include low sales price, low production cost, the possibility of oral admission, and very good membrane permeability. Both small molecules extracted naturally or chemically synthesized tend to have a competitive price advantage when compared to peptide drugs and other biologics.
A couple of benefits associated with oral administration of small molecules are better safety and improved patient compliance. Their small size also makes it possible for them to easily penetrate the cell membranes of the target intracellular molecules. However, their small size also becomes a hindrance when it comes to large surface interactions such as protein-protein interactions – PPIs.
By contrast, the unique physicochemical properties of peptide drugs including their flexible backbone and large size make it possible for them to act as potential inhibitors of PPIs. The clinical applications of small molecules may also be hampered by the low specificity compared to peptide drugs.
Therapeutic peptides suffer from two serious drawbacks, and these have always been major stumbling blocks when it comes to the development of peptide drugs. These drawbacks include-:
- Membrane Impermeability – amino acid-based therapeutics are generally known to have weak membrane permeability. It should be noted that the membrane permeability of peptide drugs depends on a variety of factors, the chief ones being the composition of the specific amino acid and the length of the peptide. It is usually impossible for peptides to move across the cell membrane in order to reach the intracellular targets. This has always been a great limitation in their potential applications in the development of peptide drugs. In a study conducted by Lau et al. in 2018, it was observed that more than 90% of the peptides that were undergoing active clinical development were designed with extracellular targets in mind. Some of these peptides included gonadotropin-releasing hormone, Glucagon-like peptide 1 (GLP1) and G-protein coupled receptors (GPCRs).
- Poor in vivo stability – the other limitation in the development of peptide drugs is the fact that peptides have very poor in vivo stability. Most of the natural peptides have chains of amino acids which are joined by amide bonds, but they lack the stability that is normally associated with the secondary or tertiary structures. It is easy to hydrolyze or destroy the amide bonds by enzymes in vivo whenever they are exposed to the environment and they are not subjected to any kind of protection. These chemical properties imply that the peptides are chemically and physically unstable. This also means that they have a short half-life and will encounter faster elimination in vivo.
The Development Path of Therapeutic Peptides: Peptide Drug Discovery
The history of peptide drug discovery can be traced back to the exploitation of natural hormones and peptides with physiological functions for treating diseases and ailments that were arising as a result of hormone deficiencies, such as the lack of proper insulin levels needed to effectively regulate the blood sugar levels in patients suffering from T1DM or T2DM.
Some of the common treatments for diabetes include the stimulation of insulin secretion-related targets such as GLP-1 receptors to produce more insulin or through insulin injection. The initial strategies used for peptide drug discovery and development included getting natural peptides and hormones or replacing the natural peptides and hormones with animal homologs such as somatostatin, GnRH, GLP-1, and oxytocin. However, the disadvantages associated with the natural peptides necessitated the optimization of their natural sequences which ultimately led to a series of natural hormone-mimetic peptide drugs.
Peptide Mimicking Hormones
GLP-1 derived peptide drugs is a 37-amino acid peptide with the ability to regulate the production and secretion of insulin, and it comes with a very short life in vivo. Much effort has gone into modifying its sequence with the goal of enhancing its stability while at the same time maintaining its potency without compromising any of its pharmacological effects. This had led to the design and development of some of the top three selling anti T2DM peptide drugs – Ozempic, Victoza, and Trulicity.
Peptide drugs derived from Gonadotropin-releasing hormone (GnRH) contain a total of ten amino acids that have been produced by GnRH neurons in the hypothalamus section of the brain. Through the modification of the native sequence, it has been possible to develop a variety of peptide drugs including degarelix and leuprolide.
Leuprolide features the same biological activities such as GnRH through the activation of GnRH receptors. It is also currently being used as a GnRH receptor agonist in the treatment of hormone-responsive prostate cancer, uterine fibroids, endometriosis, and precocious puberty. Though the sequence of degarelix has been optimized from GnRH, it normally works as a GnRH antagonist by competing for binding sites with the GnRH receptor and, as such, it is used as a potential treatment for terminal prostate cancer.
There are currently many peptide drugs pending approval that have been derived from natural hormones. These include drugs such as octreotide, which is a somatostatin mimic peptide drug currently being used in the treatment of growth hormone-producing tumors and pituitary tumors.
The Rational Design of Peptides Based on Protein-Protein Interactions
Through the development witnessed in proteomics and structural biology, many protein-protein interactions (PPIs) involved with most of the cellular and biological functions have been discovered. It is estimated that there are over 14000 PPIs which account for about 1% of all the protein-protein interactions n the human body that have been comprehensively studied to date. PPIs are also believed to have the properties to regulate a variety of essential pathways regarding human diseases and, as such, they are potential targets for drug development.
Peptides have valuable advantages as inhibitors or powerful activators of PPIs in comparison to antibodies and small molecules. Consequently, a new drug discovery technology that uses known crystal structures of PPIs has been developed: the rational designs of peptides. This is currently considered a vibrant and promising strategy for the discovery of new peptide drug candidates.
With the rational design of peptides, there is the use of computer-assisted bioinformatics technology that is based on the resolved crystal structure of the target protein-protein interactions. Computational and bioinformatics analysis of the PPIs binding interfaces makes it possible for the essential amino acid present on the two interacting surfaces to be identified. The essential amino acids play a major role in the process since they are a vital contributor to the Gibbs energy of the PPIs and due to this, they are commonly referred to as hotspots.
Usually, hotspots may be certain continuous fragments of the proteins or they may be dispersed residues present on different secondary structures of the protein. When it comes to designing the protein modulators for the PPIs, a major concern is always about the hotspots. They can be used directly with their continuous fragments or they can be used as a strategy for linking the dispersed residues like in the initial sequence.
But, there is still a need for further peptide development as well as structure optimization, including backbone modification and peptide cyclization to improve both the activity and the physiochemical properties. For instance, identifying essential peptide residues and the potential substitution of the non-essential residues through the thorough study of the structure-activity relationship, as well as the chemical modification of the sequence for a more stable peptide secondary structure may be used in enhancing the bioactivity as well as improving the physicochemical properties.
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