Peptides have emerged as an exciting class of therapeutic molecules in modern drug research. But what exactly are they?
Peptides are short chains of amino acids, essentially miniature proteins, usually containing a few to dozens of amino acids. The first therapeutic peptide, insulin, was discovered over a century ago, and peptide drugs have since become a major field.
The rapid growth today is driven by advances in peptide development processes and a recognition that peptides can hit biological targets in ways that traditional small-molecule drugs sometimes cannot.
The Peptide Drug Development Process
Creating a peptide-based drug involves multiple stages from concept to clinic. Below is an overview of the key steps in peptide development and how researchers address the unique considerations of peptides at each stage:
1. Discovery & Design
Every peptide therapeutic begins with identifying a peptide sequence that has a desirable biological effect.
This might mean discovering a natural peptide that can be repurposed as a drug, or designing a novel peptide from scratch to hit a specific target. Historically, many peptide drugs originated from natural human or animal hormones – insulin, oxytocin, vasopressin, and others were early examples.
Researchers today also use computational modeling and high-throughput screening for peptide development. At this stage, medicinal chemists will consider how modifications could improve the peptide’s stability or activity before committing to a final sequence for development.
2. Synthesis of the Peptide
Once a lead peptide sequence is chosen, the next step in peptide development is to actually produce the peptide molecule. There are two main production routes:
- Chemical synthesis
Solid-phase peptide synthesis (SPPS) is the most common lab method, involving stepwise assembly of peptides on an insoluble resin. It builds peptides one amino acid at a time: adding, de-protecting, and coupling until complete. SPPS is automated, easily incorporates modifications, and works well for peptides up to a few dozen amino acids. For very short peptides, traditional solution-phase chemistry is also effective. - Biological production
For larger or complex peptides, recombinant DNA technology can be used—employing living cells to produce the peptide. Scientists insert a gene into bacteria, yeast, or cell cultures, which then express the peptide as part of a protein that can be harvested. Afterward, the peptide is cleaved and purified. This method is common for peptides with multiple disulfide bonds or that are too long for chemical synthesis. Other biological methods include isolating from natural sources or fermentative production of cyclic peptides. While many peptides are now made by chemical synthesis, some still rely on bio-expression for large-scale manufacturing.
3. Purification & Characterization
Regardless of how a peptide is made, the crude product typically contains a mixture of correctly made peptide and various impurities. Rigorous purification is required to isolate the pure peptide in the peptide development process.
High-performance liquid chromatography (HPLC) is a workhorse technique for this purpose – it can separate the target peptide from closely related impurities based on differences in chemistry.
The purified peptide is then analyzed to confirm its identity and quality. Analytical methods like mass spectrometry and NMR are commonly used to verify the peptide’s molecular weight, amino acid sequence, and structural conformation.
For example, Neuland Labs utilizes 600 MHz NMR and LC-MS/MS for comprehensive peptide characterization in its development projects. Only after a peptide passes strict characterization (ensuring it’s the correct molecule with the required >99% purity) can it move forward as a drug candidate.
4. Optimization via Modification
One of the powerful aspects of peptide development is the ability to chemically modify peptides to improve their drug-like properties. Developers will often create analogues of the lead peptide with strategic changes:
Unnatural amino acids
Replacing certain natural L-amino acids with D-amino acids or other non-natural residues can make the peptide less susceptible to enzymatic breakdown, thereby extending its half-life.
However, such changes must be balanced, as they can sometimes reduce the peptide’s biological activity if the shape is altered too much.
Cyclization
Converting a linear peptide into a cyclic peptide can significantly enhance stability. Cyclic peptides are less floppy, which often makes them more resistant to proteases and can improve binding affinity.
Conjugation and PEGylation
Attaching large inert molecules like polyethylene glycol (PEG) to a peptide (a process called PEGylation) is a proven strategy to prolong circulation time. PEG acts as a protective shield, slowing renal clearance and degradation of the peptide.
Several peptide drugs use this approach to enable less frequent dosing. Other conjugations include adding fatty acid chains or coupling the peptide to an antibody fragment or nanoparticle – all aimed at improving stability, targeting, or delivery.
Improving delivery
If a peptide is intended for oral use or other novel routes, researchers may modify it to improve membrane permeability.
Modern peptide development is very much an iterative process: a base peptide may go through multiple rounds of tweaking and re-testing to reach an optimal balance of potency, stability, and bioavailability.
A famous case is the peptide development of GLP-1 analogs for diabetes – the natural GLP-1 hormone has a half-life of only ~2 minutes, but through amino acid substitutions and an attachment of a fatty acid chain, researchers created drugs like liraglutide and semaglutide that last for hours to days in the body.
5. Scale-Up and Manufacturing
If a peptide therapeutic shows promise in preclinical and clinical trials, production needs to be scaled from laboratory grams to multi-kilogram GMP manufacturing batches.
Scaling up peptide synthesis presents technical hurdles – reaction conditions and purification processes must be optimized to handle larger volumes while maintaining product quality and consistency.
Often, a hybrid approach is used for manufacturing longer peptides: shorter fragments are synthesized separately (which is easier and high-yield) and then these pieces are chemically ligated (condensed) together to form the full-length peptide.
This segment condensation strategy, combined with both solid-phase and solution-phase techniques, allows production of very long peptides (over 100 amino acids) that would be impractical to make in one piece via SPPS.
Finally, a regulatory package, including Chemistry, Manufacturing, and Controls data, is prepared so that the peptide drug can gain approval for commercial use. By this stage, years of peptide development work culminate in a reproducible process to supply the peptide therapeutic to the market.
Conclusion
Peptides have clearly established themselves as an important pillar of modern drug research – bridging the gap between small molecules and larger biologics with their unique advantages.
While challenges like instability and delivery continue to be addressed through clever scientific innovation, peptide therapeutics are expected to play an ever-expanding role in treating disease.
In this dynamic landscape of peptide development, pharmaceutical innovators often partner with specialized contract development and manufacturing organizations to realize their peptide projects.
Neuland Labs is a leading CDMO that has built extensive expertise in peptide synthesis, scale-up, and analytical characterization, supporting everything from early-stage custom peptide development to commercial Active Pharmaceutical Ingredients (APIs).
By leveraging such third-party expertise in peptide development – alongside ongoing advances in peptide science – drug developers can successfully translate these potent molecules from concept to clinic, bringing forward the next generation of peptide-based therapies.
FAQs
1) How is preclinical evaluation for peptide development different?
Peptide programs prioritize protease stability, half-life extension, and immunogenicity screening alongside standard efficacy/toxicity. ADME focuses on rapid clearance and tissue distribution.
2) What regulatory considerations apply to peptide APIs?
Most therapeutic peptides are regulated as chemical entities under ICH Q7/Q11, with strong CMC emphasis on sequence confirmation, isomer/truncation impurities, and potency assays. Biotech-expressed peptides introduce additional controls for residual host proteins and viral safety.
3) What is a realistic timeline to first-in-human?
For a well-defined peptide lead, expect ~12–24 months from candidate selection to Phase 1, assuming rapid synthesis, early stability/formulation work, GLP tox in two species, and GMP batch readiness without major process re-designs.
4) When should teams engage with a peptide development CDMO?
Engage a CDMO at lead nomination. Ask about peptide SPPS/LPPS experience, impurity control strategy, analytical methods (HPLC/MS), GMP readiness, scale-up track record, tech-transfer approach, and timelines for engineering, clinical, and validation batches.
