The Rise of Peptide Therapeutics [Peptide Drug Discovery – Part 1]

Proteins and peptides are the building blocks of our body (in fact of all living organisms), while amino acids are the basic units. In the recent decade, the peptide has gained enormous attention in drug discovery programs due to its exceptional success in medical science during the last few years. However, the rise of peptide therapeutics wasn’t so smooth up to the 1990s.

In this part of the Peptide Drug Discovery series, we’ll have a brief discussion about the development of peptide therapeutics from the beginning and also uncover the way through which it became a promising research direction in the present day.

Difference between Proteins and Peptides

Before entering the main discussion, I just want to give a brief note mentioning the basic difference between protein and peptide you wouldn’t be confused anyway.

Both proteins and peptides are natural polymers made of a sequential series of amino acids, which are linked together by the peptide bond. However, the major distinguishing factors between proteins and peptides are the size of the polymer. Peptides are relatively smaller that consist of between 2 and 50 amino acids, whereas proteins carry more than 50 or more amino acids in their structure.

The following discussion will be conducted on peptide therapeutics including its promising results that came to the limelight slowly but steadily.

The Beginning of Peptide Therapeutics

In the early 1900s, peptides gained little attention to the scientists who were dealing with drug discovery. The application of peptide therapeutics initiated in 1922 after extracting insulin, which exhibited promising activity for the treatment of type 1 diabetes.

The Rise of Peptide Therapeutics - Insulin
Insulin: the chemical structure and SVG image

Later, inspired by the results of insulin, a few other scientists/companies focused on synthesizing biologically relevant peptides, which resulted in the commercialization of oxytocin and vasopressin, the first synthetic hormones. However, due to the difficulties of liquid-phase synthesis of peptides, it took almost 4 decades to launch the first two synthetic hormones.

The Rise of Peptide Therapeutics -Oxytocin and Vasopressin
Chemical structure of Oxytocin and Vasopressin

The invention of solid-phase peptide synthesis (SPPS) by Robert Bruce Merrifield in 1963 was an incredible discovery in synthetic as well as peptide chemistry that remarkably fasten the synthesis of the new peptide with a much higher atom-economy. For this immerging discovery, he had been awarded Nobel Prize later in 1984.

Still, Peptide Drug Discovery Program Continued to Struggle!

Despite the lack of interest by the drug industries, scientists around the world never stopped their research with peptides. During the period of 1960-1970, the potentiality of peptides in drug discovery programs was already explored in the scientific world. Due to their high selectivity and low toxicity peptides are perfectly optimized candidates for drug development.

However, several negative properties of pure peptides also recognized at the same time, including low oral bioavailability, low plasma stability, and short circulation time. These serious drawbacks suppressed the interest of pharmaceutical industries in peptide drugs.

After the invention of the SPPS strategy, although the peptide synthesis became faster along with increased atom-economy, the process was restricted within small-scale derivation. In those days, the large-scale synthesis was still pretty expensive to make it commercially viable. Eventually, peptide-based drug discovery lost every faith from pharmaceutical industries in the ’70s up to mid ‘80s. Noticeably, that was the golden age of small molecule pharmaceuticals due to their easy access and cost-effectiveness.

The Second Wave in the History of Peptide Therapeutics

The second wave in peptide drug discovery program began in the late 1980s, which was initiated after the approval of insulin as human therapeutic in 1982 followed by the discovery of two other synthetic peptides (gonadotropin-releasing hormones) leuprolide and goserelin in 1985 and 1989, respectively.

Peptide Therapeutics - Leuprolide and Goserelin
Chemical Structure of Leuprolide and Goserelin

To secure seamless action in the human body, recombinant technology was implemented for Insulin drug development, which was the turning point in peptide drug discovery research. Inspired by the success of recombinant technology, in the late ‘80s peptide drug discovery programs started receiving fundings as well as support from biotechnology companies.

A massive increase in investment and unlimited research throughout the world in the 1990s gifted us a number of novel peptides ready for clinical trial during the period of 2000-2010.

At present 80 peptide drugs are available in the global market, around 150 peptides are in the clinical trial, and more than 600 peptides are under preclinical development. However, in the present decade peptide drug development research is steadily moving forward worldwide.

Approches that Succeed Peptide Drug Discovery Programs

From the above discussions, it can be realized that the rise of peptide therapeutics was never been a smooth process. At the mid-stage of the investigation period, most of the drawbacks of hormone therapeutic development were recognized; among those, the short metabolic half-lives of endogenous hormones were the most problematic issue.

Several medicinal chemistry approaches were employed to increase the stability, potency, selectivity, pharmacokinetics, and pharmacodynamics of the endogenous hormones, that includes:

  • Use of d-amino acids
  • Amino-terminal (N-terminal) capping
  • Extensions of N-termini or carboxy termini (C termini)
  • Selective deamination
  • Development of unnatural amino acids
  • Disulfide bond mimetics
  • As a result, desmopressin, terlipressin, carbetocin, and atosiban were established later.

The Story of Somatostatin: A high-valued Peptide

Somatostatin is another efficient peptide hormone that is capable to inhibit the secretion of growth hormone, glucagon, insulin, secretin, gastrin, and thyroid-stimulating hormone; unfortunately, the very short in vivo half-life (<3 min) of this valuable peptide remarkably reduces its pharmaceutical value. Further, in-depth research on this peptide and modifications in amino acid residues (replacement of specific residue with the N-methylated versions or introduction of d-amino acids) successfully identified the β-turn pharmacophore having higher metabolic stability.

The Rise of Peptide Therapeutics - Somatostatin
Chemical Structure of Somatostatin

Eventually, octreotide, a new peptide drug, was discovered and approved for the treatment of acromegaly, adenomas, and pancreatic, breast, and prostate tumors.

Another peptide, pasireotide was derived via N– to C-terminal cyclization of somatostatin, securing a fair increase in the half-life (12 h) compared to that of somatostatin. Lanreotide, vapreotide, etc., are some other sub-type analogs of somatostatin.

Peptide Therapeutics - octreotide and vapreotide
Chemical Structure of Octreotide and Vapreotide

Besides, several radiopharmaceutical agents were also developed from somatostatin analogs, where radioactive elements such as 111In, 90Y, 68Ga, or 99mTc were introduced as chelating groups to specific somatostatin analogs. These efforts resulted in the discovery of some tumor-detecting radiopharmaceuticals, such as indium In 111 pentetreotide, technetium Tc 99m depreotide, gallium Ga 68 DOTA-TOC, gallium Ga 68 DOTA-TATE, copper Cu 64 DOTA-TATE, lutetium Lu 177 DOTA-TATE, etc.

Peptide Therapeutics - lutetium Lu 177
Chemical Structure of Lutetium Lu 177

Among the above-listed radiopharmaceuticals, lutetium Lu 177 DOTA-TATE is the latest approval which exhibited excellent result in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors.

Development of Superantagonists

Antagonists treat diseases by desensitizing and downregulating the receptors. Rapid research has been conducted to develop superantagonists by mimicking this process in hormone/ peptide therapy.

GnRH-based drug development programs were the pioneer strategy that responded as superantagonist for the treatment of cancer, estrogen-related female disorders, delayed puberty, sex reassignment, etc., and also could be applied in in-vitro fertilization therapy.

In recent times, unnatural amino acids have been used extensively for designing new antagonists, which resulted in the approval of several drugs, such as cetrorelix, ganirelix, etc.

Peptide Therapeutics -cetrorelix and ganirelix
Chemical structure of Cetrorelix and Ganirelix

Extended Delivery System for Controlling the Doses of Peptide Therapeutics

To confirm slow-release, low doses, or long-term applicability of a drug, proper formulation securing extended delivery system are required. Such extended delivery is very common in peptide therapy, especially in the case of intramuscular or intranasal delivery.

Hydrophobic depots formulation is one of the most common methods that is used for delayed-release. Biodegradable Poly(d,l-lactic-co-glycolic acid)/poly(lactic acid) microparticle depot formulations are one such example that is capable to extend the delivery of drug concentrations once weekly, or once in a month, or even once in 6-month dosing.

Presently 8 peptide-based drugs are available in the market that are using this polymer-based vehicle for therapeutic peptide delivery.

[Continue to the Next Issue]

Website | + posts

Dr. Suvankar Das pursued his doctoral degree in Chemistry in 2015. Further, he was associated as postdoctoral researcher (Synthetic & Medicinal Chemistry) and research scientist in several institutes and companies. Presently he is associated with multiple organizations as an editorial board member and scientific consultant.

With the aim to deliver updated information about novel discoveries and unknown facts of science, Dr. Suvankar Das founded SynnBiob Science Magazine. He believes, exploring sustainable science in a divergent way is the ultimate path to create a beautiful world.

Besides his scientific journey, he is also a passionate traveler. Travel Entice (, which is his other foundation, gained immense popularity recently.

Leave a Comment