Improving Oral Peptide Delivery Through Structural Modifications

Peptide therapeutics, once a niche segment of the drug market, have taken center stage due to the success of GLP-1 receptor agonists as treatments for diabetes and weight loss. Potential applications for these and other types of peptides in a wide range of indications (eg, oncology, gastrointestinal disorders, cardiovascular conditions, and rare endocrine diseases) are also fueling growth.¹ Advances in peptide engineering, manufacturing processes, and formulation and delivery technologies are enabling more cost-effective development and production of peptide drugs with improved stability, specificity, and efficacy. As a result, the value of the global therapeutic market is estimated to be expanding at an 8.7% compound annual growth rate from $164 billion in 2026 to $294.6 billion by 2033.¹

One of the biggest hindrances to the growth of peptide therapeutics is their poor oral bioavailability, which can be as low as 1% to 2%.^2-4 Researchers have been investigating various approaches to improving the stability, solubility, and absorption of peptides with the goal of achieving performance levels for oral delivery closer to those obtained with injectable products. Use of inhibitors to prevent their degradation by enzymes and permeation enhancers that increase their passage through the intestinal epithelial layer, as well as encapsulation in various types of nanoparticles and formulation as self-emulsifying drug delivery systems, are key examples.

Chemical modification of peptides, also referred to as peptide engineering, represents another effective strategy. Lipidation, cyclization, and polyethylene glycosylation can impact the physicochemical properties of peptides, leading to improved stability and transport.^2-4

Why Chemical Modification Makes a Difference

“Peptide therapeutics play an increasingly important role in modern medicine, with the potential for high target specificity and biological activity across a growing range of diseases,” notes Jan Jezek, chief scientific officer at Arecor. However, one longstanding challenge remains: how to effectively deliver these medicines orally.

Under the biopharmaceutical classification systems, peptides typically fall into class III (low permeability, high solubility) or IV (low permeability, low solubility) due to their large size, hydrophilicity, limited membrane permeability, and susceptibility to enzymatic degradation.⁴ Added to these issues is their sensitivity to denaturation, adsorption, aggregation, oxidation, and hydrolysis during production.

Many native peptides, in fact, have limited drug-like properties, and for oral delivery 2 barriers dominate: low permeability across the intestinal wall and instability in the gastrointestinal tract, adds William Fang, vice president and head of oligonucleotide and peptide development with WuXi TIDES, WuXi AppTec.

Peptides were not designed to survive the gastrointestinal (GI) tract, Jezek explains. “When administered orally, they encounter dramatic changes in pH and a range of proteolytic enzymes that rapidly degrade them. Those that survive must then penetrate the intestinal mucus layer and cross the epithelial barrier before reaching the systemic circulation. Depending on the molecule, first-pass metabolism can pose an additional obstacle.”

For these reasons, relatively few oral peptide therapeutics have advanced to late-stage clinical development or the market. Several innovative approaches have shown promising results, though. Jezek believes no single solution will solve the problem. However, he, Fang, and Santosh Kulkarni, vice president of medicinal chemistry with Sai Life Sciences, highlight that advances in molecular engineering can make peptides more resistant to degradation and potentially more permeable. Formulation strategies and delivery technologies, meanwhile, can provide protection and enhance absorption.

Chemical modification works by shifting the peptide’s liabilities rather than by making it behave exactly like a small molecule, according to Kulkarni. “Protease-sensitive bonds can be removed or shielded; conformational restriction can reduce enzyme access; charge and hydrogen-bonding can be tuned to improve membrane partitioning; and albumin-binding or size-increasing groups can slow clearance after absorption,” he explains.

“Chemical modification is one of the most important levers for changing peptide properties at the molecular level,” Fang agrees. He uses macrocyclization, including peptide stapling, as illustrative. “Constraining the peptide’s conformation improves its resistance to proteolytic enzymes, and cyclic peptides generally offer better stability and bioavailability than linear sequences,” he says.

Chemistry rarely carries the full load, however; in practice, engineered peptides are paired with permeability enhancers and formulation approaches such as solid dispersions, self-microemulsifying systems, and oral solid or liquid dosage forms, observes Fang. He also emphasizes that even with molecule and formulation working together, oral peptide bioavailability remains modest. “That is why every incremental gain from chemical design matters,” he concludes.

Many Chemical Modifications

Structural modification of peptides can take place across all aspects of a peptide drug substance, including its backbone, side chains, and overall topology, according to Fang. According to the literature, N-methylation or acetylation, C-terminal modification, D-amino acid substitution (preparation of peptide analogs), incorporation of non-natural amino acids, cyclization, lipidation, glycosylation, pegylation, and prodrug formation are all used to improve their physicochemical properties and in vivo behavior, including extending the therapeutic half-life.^2,4-7

Some specific examples of selected chemical modifications highlighted by Fang include:

• Backbone modifications: N-methylated and other N-alkylated amino acids, Cα-methylated and other α-, β- and γ-substituted residues, and peptidomimetics and peptoids.
• Side-chain changes: phosphorylation, glycosylation, sulfation and azido functionalization, alongside lipidation and PEGylation.
• Cyclization strategies: thioether, disulfide, lactam and lactone rings; ring-closing metathesis (RCM) and click chemistry; and increasingly polycyclic architectures of roughly 15 to 28 residues.

“Mechanistically,” Fang notes, “cyclization and stapling work by constraining conformation, which improves resistance to proteases. Hydrocarbon stapling also stabilizes the α-helical structures that often mediate protein–protein interactions, which makes it well suited to targets that are hard to reach with other approaches.”

Macrocyclic peptides, which occupy a therapeutic space between traditional small molecules and larger biologics, are particularly promising for Jezek. “In addition to restricting conformational flexibility and protecting peptide termini, thereby making the molecule less accessible to proteolytic enzymes, cyclization may also improve membrane permeability for some peptides by reducing the exposure of polar groups that would otherwise impede passive diffusion across lipid membranes,” he says. He does point out, though, that cyclization does not automatically create an orally bioavailable peptide; permeability remains highly dependent on achieving the appropriate balance among polar and non-polar surfaces, structural rigidity, solubility, and target-binding properties.

Other molecular strategies can, however, contribute to optimization of stability and permeability, Jezek adds. “Incorporating unnatural amino acids can make peptides less susceptible to recognition and cleavage by naturally occurring proteases,” Jezek comments. Researchers are also investigating approaches such as masking hydrogen-bond donors, increasing lipophilicity, introducing linkers and disulfide bonds, and eliminating sequences known to be particularly susceptible to enzymatic degradation.

“The challenge is that these characteristics cannot be optimized independently,” Jezek remarks. “Increasing stability provides little benefit if a peptide cannot cross the intestinal epithelium. Increasing lipophilicity or rigidity to improve permeability can potentially affect solubility or target engagement. And improving oral exposure is of limited value if the modification compromises the pharmacological characteristics that made the peptide attractive in the first place,” he observes.

“The objective, therefore, is not simply to create the most stable peptide but to optimize stability, permeability, potency, specificity, and pharmacology simultaneously,” Jezek contends. He notes that given the multiple factors involved, computational approaches and artificial intelligence could become increasingly important in peptide engineering. “The ability to evaluate large numbers of potential structures against multiple parameters could enable researchers to optimize metabolic stability, cellular uptake and target specificity earlier and more holistically than was previously possible,” he says.

Biology and Manufacturability Determine the Best Approach

The right approach to chemical modification, in fact, emerges from the target biology, the peptide’s structure, and the practicalities of making it, according to Fang. The best approach, Kulkarni adds, is determined by the target product profile and possible product liabilities. “Important inputs include the peptide’s sequence and cleavage sites; secondary structure; molecular weight; net charge, polar surface and hydrogen-bond count; solubility and aggregation; target-binding pharmacophore; required site and duration of exposure; dose and therapeutic window; and the absorption enhancer or delivery platform being considered.”

For instance, a compact peptide with a tolerant pharmacophore may suit macrocyclization and N-methylation, Kulkarni notes. A larger soluble agonist may benefit more from selective residue substitution plus lipidation for systemic persistence. He adds that site-specific rather than global modification is generally preferred, because it preserves activity and gives a more homogeneous, viable product.

“Helical peptides that act at protein–protein interfaces, for example, are natural candidates for stapling, and the cyclization chemistry is chosen to suit the target, whether disulfide, lactam, ring-closing metathesis, click or thioether,” Fang says. Synthetic feasibility belongs in the decision from the start, he notes, because cyclization efficiency depends on conformation, ring size, steric effects, and the chemistry used, which makes the outcome hard to predict. Increasingly, the answer is found empirically. Fang highlights one oral weight-management program for which more than 1700 cyclic peptides with varied side chains and ring chemistries were synthesized and screened to identify 10 hits, 3 leads, and 2 candidates. “The preclinical candidate was selected for potency, stability, and developability together, not potency alone,” says Fang.

Indeed, chemical modification decisions are also manufacturing decisions. “The choices made during lead optimization, such as which ring chemistry, which unnatural amino acids, and how many constraints shape the impurity profile, the analytical package, and the feasibility of supply years later,” Fang explains. He adds that programs move fastest when building-block supply, process development, analytics, and formulation run in parallel instead of in sequence.

“When this approach is taken, it is possible to move an oral cyclic peptide from lead optimization to GMP readiness in about 2.5 years,” Fang states. In one oral cyclic peptide program at WuXi AppTec, this approach took the candidate from lead optimization to good manufacturing practice readiness in about 2.5 years. Its discovery-to-development hand-off took a single day, and route scouting improved crude purity by more than 70% and yield by more than 140%, according to Fang.

Advancing Peptide Engineering With Multipronged Modifications

In addition to selecting the most appropriate formulation strategies and delivery technologies, advances in peptide engineering that leverage multiple chemical modifications simultaneously is providing further improvements in the performance of orally delivered peptides. “The most promising direction is not a single new modification but combining several constraints in one molecule,” Fang says. Beyond single-ring cyclization, he notes that developers are now designing bicyclic and tricyclic peptides that pair disulfide, lactam, click, and ring-closing metathesis rings, often alongside N-alkylated or other backbone-modified residues.

The deliberate design of orally permeable macrocycles rather than reliance on a single conventional modification is, agrees Kulkarni, the most important new strategy being pursued to improve oral peptide delivery. “Combinations of noncanonical residues, backbone N-methylation, stereochemical control, and multiple ring constraints can create protease-resistant molecules that dynamically shield polar groups,” he says.

The rationale for this multi-pronged approach, Fang observes, follows from why cyclization works in the first place. “Constraining a peptide’s conformation improves its resistance to proteolysis, and stapling holds peptides in the helical shapes that engage protein–protein interfaces,” he explains.“Recent clinical and regulatory successes with targeted oral macrocyclic peptides provide the strongest validation of this design strategy,” Kulkarni adds.

Other active areas include reversible charge-masking prodrugs, lipid or bile-acid conjugates intended to exploit intestinal or lymphatic pathways, and computational approaches that jointly optimize permeability, solubility, potency, and metabolic stability, according to Kulkarni. He also notes that hydrophobic ion pairing and self-nanoemulsifying systems are being investigated as well; although, these are formulation-enabled rather than permanent changes to the peptide.

Oral peptides are also being pursued against new target classes, including pathological protein aggregation and difficult intracellular interactions in oncology, according to Fang. These more complex designs, he says, are becoming practical because of supporting advances. For instance, quantum mechanics modeling can predict whether a ring will close before synthesis begins, and modified peptides are increasingly paired with new permeability enhancers.

Clinically Meaningful Results

The advantages of chemical modification are not simply theoretical; they have been leveraged in several marketed drugs. Obvious examples include the oral GLP-1 products Rybelsus, Wegovy Pill, Ozempic Pill (all from Novo Nordisk), and Foundayo (Eli Lilly), which have been approved in the past year by the FDA.

Jezek points to Merck’s enlicitide (Lipfendra) as a good example of how sophisticated molecular engineering can translate into clinically meaningful therapies. “This highly engineered macrocyclic peptide incorporates structural modifications designed to optimize potency, stability, solubility, and oral bioavailability,” he says. Approved by the FDA in July 2026, enlicitide is the first oral PCSK9 inhibitor approved to reduce LDL cholesterol in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia.⁸

Also highlighted by Jezek is Johnson & Johnson’s icotrokinra (Icotyde), a macrocyclic peptide incorporating natural and non-canonical amino acids approved by the FDA in March 2026 for the treatment of moderate-to-severe plaque psoriasis in eligible adults and adolescents⁹, which he believes represents an important example of an engineered oral peptide successfully translating into an approved medicine.

Kulkarni, meanwhile, notes that Chiesi’s octreotide capsules (Mycapssa), approved for maintenance treatment in selected patients with acromegaly¹⁰, is an intrinsically cyclic, protease-resistant somatostatin analogue and developed as an enteric formulation with a transient permeability enhancer that demonstrates how molecule–formulation pairing can help develop peptide therapeutics for oral administration.

Limitations Must be Considered

Chemical modification requires implementation of chemical reactions to achieve the desired structural changes. While making these structural alterations can provide benefits, it can introduce other issues. Fang observes that non-commercial unnatural amino acids can introduce sourcing risk, and ring-closing reactions become harder as molecules grow more constrained.

In addition, roughly 20% of peptides are hydrophobic enough that synthesis needs excess reagents and long reaction times and produces truncated products, which complicates purification and scale-up, according to Fang. Furthermore, he notes that each additional modification adds analytical work, from quantifying D-isomer impurities to confirming the sequences of multicyclic structures. Finally, with demand for metabolic-disease peptides at the metric-ton scale, every inefficiency is magnified at scale.

Beyond these manufacturing challenges, Kulkarni points to the existence of multi-parameter trade-offs and the narrow design space available as key limitations in peptide engineering. He outlines the following issues:

• Added hydrophobicity may improve permeability but worsen solubility, aggregation, and formulation.
• Steric shielding may impair potency and cyclization can lock an inactive conformation.
• Substitutions can create new metabolites or immunogenic epitopes potentially adding additional steps for derisking such challenges.

On the flip side, higher potency and longer half-life can make very low oral bioavailability clinically useful. “The trade-off is that improving permeability with impact on solubility and receptor affinity must be viewed as one component of an integrated product development for oral peptide delivery,” Kulkarni says.

Formulation Strategies Can Help

Chemical modification is not always possible or even the best approach, however. “Sophisticated molecular design is particularly powerful when developing a new therapeutic from the outset because researchers can optimize multiple characteristics during discovery, but modifying an existing peptide drug substance is not always desirable or necessary,” Jezek says. That is because many existing peptides already possess well-understood biological activity and established therapeutic value. Their limitations may lie primarily in their stability, solubility, concentration, route of administration, or other delivery characteristics.

“In these situations,” Jezek comments, “formulation provides an opportunity to change how the therapeutic behaves as a medicine without changing the active molecule itself, a strategy that can be particularly valuable when working with molecules for which efficacy and safety are already well characterized.” Rather than redesigning the peptide, formulation scientists can seek to manipulate the environment around it, for example, protecting it from degradation, maintaining solubility, controlling local pH, or facilitating uptake. “They can,” he says, “help with increasing stability, appropriate dissolution, and delivery to the relevant absorption site so adequate uptake occurs across the intestinal epithelium,” he notes.

One example highlighted by Jezek is permeation enhancers, which can temporarily facilitate transport across the epithelial barrier. He emphasizes, however, that simply combining a peptide with a permeation enhancer does not guarantee successful delivery. “The peptide and enhancer must reach the appropriate location at the appropriate concentrations and at approximately the same time,” Jezek explains.

Peptide Engineering Part of a Holistic Strategy

The progress in oral peptides is genuinely exciting for Jezek, Fang, and Kulkarni. Macrocyclization, unnatural amino acids, conformational engineering, and computational drug design are creating molecules with properties that would have been extremely difficult to achieve previously, according to Jezek. At the same time, the relatively small number of oral peptide therapies that have successfully reached patients is a reminder of the complexity of the challenge, he observes.

No single chemical modification or formulation technology is likely to help peptides survive the harsh environment within the GI tract, withstand enzymatic degradation, reach the appropriate site, and cross mucus and epithelial barriers to achieve sufficient systemic exposure and simultaneously retain their potency, specificity, and safety. It is therefore important, Jezek states, not to treat molecular engineering and formulation as competing strategies. “Both the therapeutic’s chemical structure and its delivery formulation can be critical to achieving sufficient stability and uptake,” he comments.

Kulkarni, meanwhile, emphasizes 3 key points regarding improvement of oral peptide delivery. First, “oral bioavailability” is not the only success metric: exposure variability, food effects, dose burden, adherence, and local gastrointestinal safety may determine clinical usefulness. Second, potency and systemic half-life are often as important as permeability; an exceptionally potent, long-lived peptide may succeed with low absolute absorption. Third, development should begin with an integrated target product profile and use parallel assays for proteolysis, solubility, aggregation, epithelial transport, target potency and pharmacokinetics. The main takeaway from Kulkarni is, “Multi-parameter and multi-dimensional optimization is the most viable approach for successful oral delivery of peptide therapeutics.”

Jezek agrees. “The future of oral peptide delivery may depend less on finding one breakthrough technology and more on bringing together advances in molecular engineering, formulation science, and drug delivery. As increasingly sophisticated peptides progress through clinical development, the ability to optimize these elements together will be critical to translating promising peptide candidates into safe, effective, and convenient oral medicines,” he concludes.

References

1. Grand View Research. Peptide Therapeutics Market (2026 - 2033). Grand View Research. Accessed October 30, 2026. https://www.grandviewresearch.com/industry-analysis/peptide-therapeutics-market
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3. Dadge SD, Mishra S, Khan S, et al. Oral peptide delivery reimagined: molecular barriers, formulation strategies, and the rise of computational design. Int J Pept Res Ther 2025 31, 101. doi:10.1007/s10989-025-10763-6
4. Kshitis chandra baral and ki young choi, barriers and strategies for oral peptide and protein therapeutics delivery: update on clinical advances. Pharmaceutics 2025 17(4), 397. doi:10.3390/pharmaceutics17040397
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6. Qinfu Zhao, Xu Zhu, Shuang Cai, and Long Wan Long Wan et al. Strategies for overcoming multiple barriers of oral administration of protein and peptide therapeutics. Materials Today Bio 2026. 37:102763. doi:10.1016/j.mtbio.2026.102763
7. Saša Vukmirović,et al. Emerging technologies for oral peptide delivery: from bioinspired systems to smart device-assisted drug delivery. Pharmaceuticals. 2026 19(9):1328. doi:10.3390/ph19091328
8. FDA approves first oral PCSK9 inhibitor to lower LDL cholesterol in adults with high cholesterol. News News release. FDA. July 17, 2026. Accessed October 22, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-pcsk9-inhibitor-lower-ldl-cholesterol-adults-high-cholesterol
9. FDA approval of Icotyde (icotrokinra) ushers in new era for first-line systemic treatment of plaque psoriasis with a targeted oral peptide. News release. Johnson & Johnson. March 18, 2026. Accessed October 22 2026. https://www.jnj.com/media-center/press-releases/fda-approval-of-icotyde-icotrokinra-ushers-in-new-era-for-first-line-systemic-treatment-of-plaque-psoriasis-with-a-targeted-oral-peptide
10. Chiasma announces FDA approval of MYCAPSSA® (octreotide) capsules, the first and only oral somatostatin analog. News release. Chiasma. June 26, 2020. Accessed October 22, 2026. https://www.biospace.com/chiasma-announces-fda-approval-of-mycapssa-octreotide-capsules-the-first-and-only-oral-somatostatin-analog