Peptide drugs research
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Peptide drugs research explores the discovery, development, and delivery of therapeutic peptides for medical use.
Peptide drugs research explores how scientists discover, optimize, and deliver therapeutic peptides for medical use. Over the past hundred years, the field has expanded rapidly. Since insulin entered clinical practice, more than 80 peptide drugs have reached the market. These products support treatments across diabetes, cancer, osteoporosis, multiple sclerosis, AIDS, and chronic pain. Peptides also remain a major focus in the post-genetic era. A review in Nature Reviews Drug Discovery titled “Trends in peptide drug discovery” summarizes key directions in peptide drug development.
Milestones in the Development of Peptide Drugs
In 1922, researchers introduced the first peptide drug, insulin. They originally extracted it from cattle and pig pancreas to treat diabetes.
In 1954, chemist Vincent du Vigneaud completed the first total synthesis of oxytocin and vasopressin. This work earned the 1955 Nobel Prize in Chemistry.
In 1963, scientists created solid-phase peptide synthesis (SPPS). This method automated peptide synthesis by assembling amino acids on a solid support. As a result, teams accelerated peptide drug development.
In the 1980s, recombinant technology enabled larger-scale peptide production. Even so, peptide drugs faced a key limitation. Their short plasma half-life and fast renal filtration reduced exposure. Researchers responded by increasing molecular weight through covalent linkage with lipids, proteins, or polyethylene glycols (PEGs). New screening techniques and chemical approaches continue to strengthen peptide drug development (Figure 1).
Peptide Drug Market
Peptide therapeutics fill the gap between small-molecule chemical drugs and large-molecule biologics. As a result, peptide drugs research has supported steady global growth in approvals over the last 60 years. Reports show an average annual growth rate of 7.7% (Figure 2b).
In 2019, global peptide drug sales exceeded $50 billion. That total represented about 5% of the worldwide pharmaceutical market (Figure 2a). Insulin and its analogs contributed roughly 50% ($25 billion). GLP-1 receptor agonists followed, including dulaglutide ($4.4 billion) and liraglutide ($4.1 billion) (Table 1).
Most approved peptide therapeutics act as agonists (Figure 2c). Endocrinology, metabolism, and oncology remain the most common indication areas (Figure 2d).
R&D of Peptide Hormones
Early twentieth-century research emphasized human signaling hormones. Endogenous peptide hormones often last only minutes in plasma, which limited clinical use.
Scientists therefore applied medicinal chemistry to improve stability and performance. Somatostatin and insulin provide representative examples. Teams used point mutations, N-terminal or C-terminal extensions, and peptide cyclization. They also attached long-chain aliphatic hydrocarbons. These modifications improved stability, potency, and selectivity. In turn, several peptide drugs reached successful commercialization (Figure 3).
Peptides of Natural Origin
Cyclosporine (Figure 4a) is a peptide isolated from fungi. It is a neutral, hydrophobic cyclic peptide with 11 residues. Nitrogen methylation and its cyclic structure help resist protease hydrolysis. Hydrophobicity and conformational flexibility also improve oral bioavailability.
Regulators approved cyclosporine as an immunosuppressant in 1983. This milestone demonstrated the medicinal value of natural products. It also highlighted the potential for peptides and peptidomimetics to become oral agents.
Exenatide (Figure 4b) comes from venomous lizards. Regulators approved it in 2005 for type 2 diabetes. It became the first highly successful GLP-1 receptor agonist. Human GLP-1 (7–37) degrades quickly due to DPP-4 activity, and kidneys eliminate it within 1–2 minutes. Exenatide shares 53% homology with human GLP-1 (7–37). It also resists DPP-4 degradation and shows lower renal elimination.
Strategies for Peptide Drug Discovery
Modern peptide drugs research relies on two important discovery engines: venomics and display technologies. Venomics uses bioinformatics to analyze genomic and transcriptomic data from venomous species. Researchers also examine proteomic data from crude venom samples. This approach identifies many peptide sequences. Teams then obtain candidates through synthesis or recombinant production and screen them against targets.
Display technologies include phage display, yeast display, mRNA display, ribosome display, and DNA display (Figure 5). These methods connect peptide phenotype with genotype (DNA or RNA). They can generate huge libraries (10¹⁰–10¹⁵) and enable screening against therapeutic targets. After teams identify high-affinity leads, medicinal chemistry improves drug-forming properties.
Medicinal Chemistry Strategies for Peptide Drugs
Traditional medicinal chemistry strategies remain effective. These approaches include N-terminal acetylation, N-methylation, D-amino acids, unnatural amino acids, and amide bond mimics. Examples include thioamides, mimetic peptides, and β-amino acids (Figure 6). These tools regulate metabolic stability and bioavailability, and they continue to play a central role.
New chemical modification methods also support peptide design. Teams increasingly apply N- to C-terminal cyclization, disulfide bond mimics, and α-helical stapling. They also develop embellished peptides to improve druggability.
Advances in Peptide Drug Delivery Technology
Most peptide drugs require injection, which reduces patient compliance and increases needle-related waste. Therefore, researchers continue to develop non-injectable delivery options.
Various pump systems offer alternatives to injections, including microtechnology-based implantable pumps. These systems can control delivery precisely, but implantation remains invasive and requires refilling. Needle-free jet injectors provide another option. However, they can cause pain or bleeding, and dosing control can be limited.
Other approaches aim to increase skin penetration, including skin-penetrating peptides, ultrasound, and electric fields. Pulmonary and nasal delivery also provide potential routes. Even so, safety and delivery efficiency remain key constraints.
Oral delivery attracts strong interest, but challenges remain. Enzymatic digestion in the GI tract and limited epithelial penetration restrict bioavailability. One clinically successful approach uses an osmotic enhancer, as demonstrated by semaglutide. Additional strategies include pH modulation, mucus-permeation agents, enzyme inhibitors, hydrogels, and enteric devices. Intracellular protein–protein interactions (PPI) also represent important targets. Since many peptides show low membrane permeability, researchers developed cell-penetrating peptides (CPPs) to support intracellular delivery.
Prospects for Peptide Drug Development
Over the last 60 years, the field has addressed many challenges. Even so, peptide drug development still has room to improve. Delivery, formulation, and medicinal chemistry have progressed, yet about 90% of peptide drugs still rely on injection. Limited oral bioavailability remains a major constraint.
High R&D costs and unrealistic revenue expectations can also slow development. Nevertheless, peptide drugs research continues to advance, and market demand keeps growing. Therefore, selecting appropriate therapeutic areas remains crucial for future peptide drug development.