Beyond the Basics: How to make peptides work better?

October 6, 2025 •

5 min read

While over 120 peptide drugs are now on the market, many therapeutic peptides face challenges such as poor stability and rapid clearance. The pharmaceutical industry continuously develops novel strategies to overcome these limitations, providing various methods for how to make peptides work better through enhanced effectiveness and bioavailability.

Quick Summary

Therapeutic peptides frequently suffer from low bioavailability and short half-lives due to metabolic instability and rapid elimination. This can be addressed with strategic chemical modifications, innovative delivery systems, and advanced formulation techniques to significantly improve their efficacy and duration of action.

Key Points

Amino Acid Modification: Replacing L-amino acids with D-amino acids or non-natural counterparts makes peptides more resistant to enzymatic breakdown and extends their half-life.
Terminal Protection: Acetylation of the N-terminus and amidation of the C-terminus prevent degradation by exopeptidases, significantly increasing peptide stability.
PEGylation: Attaching polyethylene glycol (PEG) increases the peptide's size, reducing renal clearance and shielding it from proteases to extend its circulation time.
Lipid Conjugation: Attaching fatty acids allows peptides to bind to endogenous plasma proteins like albumin, thereby increasing their half-life and improving membrane permeability.
Advanced Delivery Systems: Nanocarriers and microemulsions protect peptides and enhance absorption, while ingestible devices offer innovative approaches for oral administration, bypassing major physiological barriers.
Cyclization: Constraining the peptide's structure into a loop enhances stability against enzymatic degradation and can lock it into a more pharmacologically active conformation.

The Challenge of Peptide Therapeutics

Peptides are potent and selective therapeutic agents, but their inherent properties pose significant hurdles for clinical use. As protein fragments, they are highly susceptible to rapid breakdown by proteases throughout the body, including in the liver, kidneys, and gastrointestinal tract. This metabolic instability leads to very short half-lives, often just minutes, necessitating frequent administration, typically via injections. Furthermore, their large molecular size and hydrophilic nature result in poor membrane permeability, limiting their ability to cross biological barriers and be absorbed, particularly for oral administration. To maximize their therapeutic potential, scientists employ a variety of advanced strategies aimed at increasing stability, prolonging circulation time, and improving delivery.

Chemical Modification Strategies

Modifying the peptide's chemical structure is a powerful approach to improve its pharmacokinetic properties without relying solely on delivery systems. These modifications can enhance resistance to enzymatic degradation, increase binding affinity, or improve interaction with biological membranes.

Amino Acid and Backbone Modifications

By altering the fundamental building blocks or structure of the peptide, stability can be dramatically increased.

D-Amino Acid Substitution: Natural peptides are composed of L-amino acids. Replacing one or more of these with their mirror-image D-amino acids can make the peptide unrecognizable to many proteases, thereby increasing its stability and extending its half-life. Octreotide, a somatostatin analog, uses D-amino acids to achieve a much longer half-life than its natural counterpart.
N-Methylation: Substituting a hydrogen atom on the peptide backbone with a methyl group can increase protease resistance and improve membrane permeability. This modification alters the peptide's conformation, making it less recognizable to enzymes while potentially enhancing its interaction with membranes.
Incorporation of Non-natural Amino Acids: Synthetically derived amino acids that are not found in nature can be incorporated to create more stable peptides. These non-proteinogenic amino acids can resist proteolytic breakdown and improve pharmacokinetic properties.

Terminal Modifications

Proteases known as exopeptidases cleave amino acids from the ends of peptide chains. Protecting these termini can prevent this degradation.

N-Terminal Acetylation: Adding an acetyl group (CH₃CO-) to the N-terminus of the peptide can block degradation by aminopeptidases.
C-Terminal Amidation: Converting the carboxylic acid at the C-terminus to an amide group (-CONH₂) can protect against cleavage by carboxypeptidases.

Cyclization

Cyclic peptides are formed by creating a bond between the ends of the peptide chain (head-to-tail), or between a terminus and a side chain. This structural constraint offers multiple benefits:

Increased Stability: The lack of accessible termini makes cyclic peptides highly resistant to exopeptidases.
Enhanced Receptor Affinity: The rigid conformation can lock the peptide into a biologically active shape, increasing its binding affinity and selectivity for its target receptor. Two-thirds of all approved therapeutic peptides are cyclic.

Conjugation with Polymers or Lipids

Attaching larger molecules to the peptide is a common method for improving efficacy.

PEGylation: Covalent attachment of polyethylene glycol (PEG) increases the peptide's hydrodynamic volume, which reduces its rate of renal clearance and extends its circulation time. The bulky PEG polymer also sterically shields the peptide from proteolytic enzymes, further increasing stability.
Lipidation: Attaching lipid or fatty acid chains (e.g., palmitic acid) to the peptide increases its hydrophobicity, allowing it to bind to plasma proteins like albumin. This prolongs its half-life and can also improve membrane permeability.

Advanced Delivery Systems and Formulation

Beyond modifying the peptide itself, manipulating its formulation and delivery method can significantly impact its performance.

Nanocarriers

Encapsulating peptides within nanostructures offers protection and targeted delivery.

Polymeric Nanoparticles: These systems can protect peptides from enzymatic degradation and control their release rate over time.
Lipid-based Nanocarriers (Liposomes, Microemulsions): Encapsulating peptides in lipid-based systems can enhance solubility and protect against degradation in the GI tract, offering a potential path for oral delivery.

Fusion Proteins

By fusing a therapeutic peptide to a larger, inert protein, its pharmacokinetic properties can be improved by leveraging the natural properties of the carrier protein.

Albumin Fusion: Fusing a peptide to human serum albumin significantly increases its size and takes advantage of albumin's long half-life in the bloodstream.
Fc Fusion: Attaching a peptide to the Fc region of an antibody leverages the neonatal Fc receptor (FcRn)-mediated recycling pathway, extending the peptide's plasma half-life.

Oral Delivery Strategies

While oral delivery remains a major challenge, innovative approaches are paving the way for non-invasive peptide administration.

Permeation Enhancers: Co-formulating peptides with substances that temporarily increase the permeability of the intestinal lining (e.g., bile salts, specific fatty acids) can boost absorption. The oral GLP-1 agonist semaglutide uses this approach.
Enzyme Inhibitors: Adding enzyme inhibitors to an oral formulation can protect the peptide from degradation by gastrointestinal proteases.
Ingestible Devices: Innovative technologies like ingestible, self-orienting millimeter-scale applicators (SOMA) physically inject the peptide into the intestinal wall after oral intake, bypassing many biological barriers.

Comparison of Key Enhancement Strategies


Strategy	Primary Mechanism	Half-Life Extension	Stability	Bioavailability	Administration Route	Potential Drawbacks
D-Amino Acid Substitution	Confers resistance to proteolysis	Significant	High	Improved (depending on route)	Injections	Potential change in activity or immunogenicity
PEGylation	Increases hydrodynamic volume, steric shielding	Significant	High	Poor for oral, good for injection	Injections	Potential loss of potency, non-biodegradable PEG accumulation
Lipidation	Albumin binding, increased hydrophobicity	Significant	High	Improved (oral and injection)	Injections, oral	Reduced receptor affinity, potential toxicity
Cyclization	Conformation constraint	Significant	High	Poor for oral, good for injection	Injections	Complex synthesis, potential loss of activity if constrained incorrectly
Nanocarriers	Encapsulation, controlled release	Variable	High	Improved for oral	Oral, injections	Limited drug loading, manufacturing complexity, potential aggregation
Albumin/Fc Fusion	High molecular weight, FcRn recycling	Significant	High	Poor for oral, good for injection	Injections	Complex fusion protein production, potential immunogenicity

Conclusion

The optimization of peptides has progressed significantly from early discovery to the development of sophisticated modifications and delivery systems. The strategies for how to make peptides work better are diverse and can be tailored to the specific therapeutic goal, target, and desired route of administration. By addressing inherent limitations such as low stability and poor bioavailability, these methods have enabled the development of numerous successful peptide therapeutics, from insulin analogs with longer half-lives to novel oral formulations for chronic disease management. Continued innovation in chemical modifications, advanced drug delivery systems, and formulation science promises to further unlock the vast potential of peptides in medicine.

One resource that details these strategies is a review article on improving peptide stability and delivery, available at the National Institutes of Health website.

Frequently Asked Questions

The half-life of a peptide can be increased through several strategies, including PEGylation, lipidation, fusion with albumin or Fc fragments, and incorporating D-amino acids or other stabilizing modifications that make it resistant to enzymatic degradation.

While injection is the most common route due to bioavailability issues with other methods, it is not the only option. Researchers are developing advanced delivery systems like nanocarriers, oral formulations with permeation enhancers, and ingestible devices to enable non-invasive administration.

Most peptides have very low oral bioavailability because they are easily broken down by digestive enzymes and poorly absorbed through the intestinal walls due to their large size and hydrophilicity. This makes standard oral delivery ineffective for most peptides.

D-amino acids are used to increase a peptide's stability by making it resistant to proteolytic degradation. Since most proteases in the body recognize and cleave L-amino acids, the D-form is not recognized, thus prolonging the peptide's duration in the body.

PEGylation helps peptides work better by extending their half-life and improving stability. By attaching a large, biocompatible polymer like PEG, the peptide's size increases, reducing its clearance by the kidneys and sterically hindering proteases from degrading it.

Cyclization improves a peptide's effectiveness by increasing its stability against enzymatic degradation, especially by exopeptidases that cleave peptide ends. It also introduces conformational constraints that can lock the peptide into a more active shape, enhancing binding affinity to its target.

Permeation enhancers are excipients used in formulations, particularly for oral delivery, that increase the permeability of biological barriers. By temporarily and reversibly modifying the intestinal lining, they can improve the absorption of poorly permeable peptides into the bloodstream.