The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. The integration of novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, and artificial intelligence have significantly expedited the development of groundbreaking peptide-based drugs, effectively addressing the obstacles associated with their character, such as the rapid clearance and degradation, necessitating subcutaneous injection leading to increasing patient discomfort, and ultimately advancing translational research efforts. Peptides are presently employed in the management and diagnosis of a diverse array of medical conditions, such as diabetes mellitus, weight loss, oncology, and rare diseases, and are additionally garnering interest in facilitating targeted drug delivery platforms and the advancement of peptide-based vaccines. This paper provides an overview of the present market and clinical trial progress of peptide-based therapeutics, delivery platforms, and vaccines. It examines the key areas of research in peptide-based drug development through a literature analysis and emphasizes the structural modification principles of peptide-based drugs, as well as the recent advancements in screening, design, and delivery technologies. The accelerated advancement in the development of novel peptide-based therapeutics, including peptide-drug complexes, new peptide-based vaccines, and innovative peptide-based diagnostic reagents, has the potential to promote the era of precise customization of disease therapeutic schedule.
Since the introduction of insulin in 1922, peptide drugs have become a promising modality in human therapeutics.1 Peptides offer the potency of biologics yet retain drug-like properties for oral availability and tissue penetration. Their superior specificity in targeting interactions, tunable half-lives, and typically lower toxicity and immunogenicity give peptides advantages over other modalities.2,3 Manufacturing peptides also costs less than protein therapeutics.4 With precise rational design and advances enabling improved bioavailability, peptide drugs are poised to overcome limitations of traditional small molecules and biologics.3
Historically, early peptide drugs were primarily sourced from specific animals, including reptiles, amphibians, arachnids, gastropods, and venomous mammals.5 However, the rarity of these animals and the challenges associated with extracting complex compounds from them hindered peptide drug development for several decades.6,7,8,9 It wasn't until the 1950s, with the emergence of peptide synthesis technologies, that peptides experienced accelerated advancement. Pioneering breakthroughs, such as Vincent Du Vigneaud's synthesis of oxytocin and vasopressin10,11,12 and Robert Merrifield's solid-phase peptide synthesis,13 paved the way for large-scale peptide production and the approvals of pioneering peptide drugs like goserelin for cancer in 198914 and enfuvirtide for HIV in 2003.
Today, with nearly 100 approved peptide drugs worldwide and ongoing transitions from preclinical to clinical trials, the peptide therapeutics market continues to grow.15 Significant advancements include the approval of semaglutide (Rybelsus®, Novo Nordisk A/S) as the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for managing type 2 diabetes mellitus (T2DM) and weight loss.16,17 Sales data from 2024 highlights the market dominance of semaglutide formulations, with semaglutide injections (Ozempic®) led peptide drug sales, totaling $138.90 hundred million USD. Other semaglutide formulations followed suit, with injectable Trulicity® at $71.30 hundred million USD and oral Rybelsus® at $27.20 hundred million USD (Fig. 8a), reflecting the growing demand for peptide therapeutics.
Nowadays, research efforts in peptide development continue to advance rapidly. In November 2023, Eli Lilly introduced tirzepatide (Mounjaro®/Zepbound®), the pioneering dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA for weight management and glycemic control. It demonstrated superior performance in the SURPASS phase III trials over single receptor agonists like dulaglutide and semaglutide.18 Moreover, promising candidates are emerging, such as retaglutide for treating T2DM, fatty liver disease, and obesity by targeting the glucagon receptor (GCGR), gastric inhibitory polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R).19 Additionally, diagnostic applications like the first peptide radiopharmaceutical [68Ga]Ga-DOTA-TOC for diagnosing somatostatin receptor-positive neuroendocrine tumors (NETs) underscore the versatility of peptide-based technologies.20 To provide a clear presentation of the boom in peptide drug research, we have updated the data on marketed peptides and clinical trials from Wang et al.'s recent study2 (Table 3).
Despite the advancements, challenges remain, particularly concerning the rapid clearance and degradation of peptide drugs, necessitating subcutaneous injection and increasing patient discomfort. However, ongoing developments in structural modifications and delivery systems hold promise for enabling oral peptide formulations with enhanced stability, bioavailability, and patient compliance.21 Notably, cell-targeting peptide (CTP)-based platforms and peptide-drug conjugates (PDCs) show particular promise in overcoming challenges associated with traditional small molecule therapies, enhancing efficiency, and reducing adverse effects,22,23,24,25,26,27 with multiple platforms now in clinical trials (Tables 5 and 6).
Furthermore, peptide innovation extends to the vaccine field, where peptide-based subunits offer heightened specificity, safety, and quality control compared to traditional whole-pathogen vaccines,28 transitioning vaccine development from the empirical whole-pathogen era to the defined subunit era. This transition has enabled the proliferation of preclinical trials for peptide vaccines. During the singular year span of 2023–2024, over 200 clinical trials involving peptide vaccines for infectious diseases and cancer prevention and treatment were documented on ClinicalTrials.gov. Here, we provide updated phase III trial data up to 2024 (Table 7).
This review aims to provide a comprehensive analysis of the current status of peptide-based drug development (Fig. 1), emphasizing recent therapeutic advances, delivery systems, and vaccine innovations. Additionally, we discuss future advancements and obstacles in peptide therapeutics, highlighting the ongoing evolution of this promising field.
Peptides as therapeutic agents trace back to 1922, when Dr. Frederick Banting and colleagues first extracted insulin from animals and applied it in the treatment of type I diabetes.29 Since then, peptides as therapeutic agents have played a pivotal role in human physiology, serving as hormones, neurotransmitters, growth factors, antimicrobials, and vaccines, among other functions.30,31,32,33,34
Peptides represent a discrete family of pharmacological substances that lie between tiny molecules and proteins in molecular weight, yet display distinctive biological and physicochemical characteristics (Fig. 2). Therapeutic peptides are a kind of amino acid sequences that combine properties from large proteins or other biologics with small molecule medications.3,35 Typically, these sequences have fewer than 50 residues in their chain. Peptides have advantages over proteins and antibodies, including lesser immunogenicity and lower cost of manufacture. The attachment of peptides to specific receptors elicits subsequent physiological responses, similar to the mechanism of action observed in protein and antibody medications. Peptides, on the other hand, can penetrate tissues more deeply because of their smaller size. Furthermore, peptides typically have fewer side effects because they are less immunogenic than therapeutic proteins and antibodies.36,37 Chemical synthesis is widely regarded as the 、the most advanced technology for the production of therapeutic peptides particularly following the advent of solid-phase peptide synthesis (SPPS).38 The primary advantages of SPPS are the facilitation of efficient separation of peptide products from impurities and byproducts.39 Synthetic therapeutic peptides are a great option due to their lower cost and higher quality control compared to peptides or proteins obtained through enzymatic processes or recombinant technology. Furthermore, therapeutic peptides usually have a length of 10–50 amino acids, whereas antibodies have a binding site of 75 kDa.40,41,42 This means that peptides have higher specific activity per unit mass (15–60 times higher), which lowers the cost per unit of active medicine. Peptides are also less expensive commercially since they are more stable and may be kept at room temperature.43
Therapeutic peptides offer several advantages compared to traditional small molecule pharmaceuticals. First of all, peptides typically represent the smallest functional components of proteins, thereby exhibiting heightened selectivity and specificity compared to small molecule drugs, consequently reducing the likelihood of off-target adverse reactions.44 Second, the degradation products of peptides in the body are amino acids, thereby diminishing the likelihood of systemic toxicity.45 Thirdly, peptides seldom ever accumulate in tissues because of their brief half-life.46 Due to its limited range (300–1000 A^2), small molecule drugs are difficult to effectively inhibit major biomolecular surface contacts, including protein-protein interactions (PPIs, contact area 1500–3000 A^2). Consequently, small molecule drugs encounter the challenge of effectively engaging key contact regions, thereby resulting in unintended off-target effects.47,48 Peptides possessing greater molecular dimensions and increased conformational flexibility relative to small molecule drugs may offer a solution to the challenge. Monoclonal antibodies are also a class of PPI inhibitors. Peptides exhibit greater cellular uptake and affinity for intracellular receptors compared to monoclonal antibodies, thereby enhancing their potential for biological activity. Our group conducted a review of peptide drug studies focused on targeting PPIs, including MDM2/p53, Keap1/Nrf2, and PD-1/PD-L1.49
Because of their instability in vivo and inadequate capacity to cross cell membranes, peptides present difficulties when being used in clinical settings. The main reason for this is that peptides have a lot of amino and carboxyl groups, which are difficult for them to pass lipid-based membrane structures since they frequently exhibit hydrophilicity, strong hydrogen bonding capacity, and low lipophilicity.50,51 In addition, due to their limited stability in the body, peptides are rapidly degraded by digestive enzymes in the gastrointestinal tract. As a result, they are removed from circulation within minutes. Large-scale protein hydrolysis and/or quick clearance in the liver, kidneys, or blood are the primary causes of this phenomena. It is worth noting that, with few exceptions (such as cyclosporine A), the bioavailability of most peptides following oral administration is less than 1%.52 This is primarily due to enzymatic degradation and pH-mediated hydrolysis in the gastrointestinal tract and liver, leading to low absorption rates and high first-pass effect.53 Consequently, commercially available peptides are primarily delivered subcutaneously, limiting the feasibility of more compliant oral delivery.54
The successful translation of peptide therapeutic candidates is dependent on high bioavailability and biodistribution, which include absorption and transport across biological membranes and cellular barriers.55 Solubility, lipophilicity, hydrogen bonding, chemical stability, and metabolic stability are all factors that influence these traits. Thus, peptide optimization is required, and chemical optimization procedures for therapeutic peptides are based on studies of structure-activity relationships (SAR) and/or quantitative structure-activity relationships (QSAR) of newly synthesized peptides. The goal i
