Peptide drug discovery is the process of designing, synthesising, testing and optimising peptide molecules to investigate biological targets or develop therapeutic candidates. Depending on the programme, peptides can be used for target validation, screening, structure-activity relationship (SAR) studies, optimisation and therapeutic development.
Peptides occupy a distinctive chemical and pharmacological space between small molecules and larger biologics, combining high-affinity target recognition with substantial scope for sequence-level optimisation.
It provides a powerful route to interrogating, and potentially modulating, targets and interaction surfaces that remain difficult to address with conventional small-molecule approaches. That capacity for precise molecular recognition, combined with the flexibility to modify sequence and structure, gives researchers multiple ways to investigate and optimise biological activity.
Peptide therapeutics continue to play an important role in modern drug development, with recent regulatory approvals highlighting the continued interest in peptide-based medicines. Read the 2025 review of peptide drug approvals.
For scientists, the value of peptides lies not simply in being a distinct drug modality, but in what their sequence, structure and chemistry allow researchers to investigate and optimise.
In this article, we take a closer look at the peptide drug discovery journey – from design and synthesis through screening, optimisation and the development of peptide candidates.
For researchers working with external partners, peptide drug discovery services can support this workflow across peptide design, synthesis, screening and optimisation.
Table of Content
1. Why Peptides Matter in Drug Discovery?
2. How Are Peptides Used in Drug Discovery?
-Target Validation and Mechanistic Studies Peptides help researchers investigate target biology, study molecular interactions and evaluate whether modulating a pathway produces the expected biological response.
-Screening and Hit Identification
-What Is Peptide SAR?
-Protein-Protein Interaction Research
-Peptide-Drug Conjugates and Targeted Approaches
3. What Are the Advantages of Peptides in Drug Discovery?
– Target Specificity
– Larger Interaction Surfaces
– Sequence-Level Optimisation
– Structural and Chemical Flexibility
4. Peptides vs Small Molecules: What Is the Difference?
5. What Are the Key Challenges of Peptide Drug Discovery?
– Proteolytic Stability
– Half-Life and Clearance
– Permeability
– Oral Delivery
6. How Are Peptides Optimised to Overcome These Challenges?
7. What to Consider Before Starting a Peptide Drug Discovery Project?
– Sequence and Structure
– Quantity and Purity
– Analytical Requirements
– Downstream Application
– Timeline
8. How to Select a Custom Peptide Synthesis Partner?
9. How o2h Discovery Support Peptide Drug Discovery and Research?
– Peptide Synthesis and Automation
– Purification and Analytical Characterisation
– Peptide Formats and Modifications
10. Frequently Asked Questions
11. Conclusion
Why Peptides Matter in Drug Discovery?
Peptides form specific interactions with receptors, enzymes and other proteins involved in biological processes. This makes them useful as research tools as well as potential starting points for therapeutic development.
One important area is protein-protein interaction (PPI) research. Many PPIs involve broad, extended interfaces that conventional small molecules struggle to address. Peptides can provide extended interaction surfaces, making them useful for investigating biological interactions that may be challenging to address with conventional small molecules.
Peptides also provide considerable scope for optimisation. Researchers can modify amino acid sequences, incorporate non-natural amino acids, and alter or constrain peptide conformation to study how structural changes influence activity, selectivity, stability, and other properties.
This creates an iterative discovery cycle:
Design → Synthesis → Testing → Analysis → Optimisation → Resynthesis
This iterative cycle is why peptide synthesis can be an important part of peptide drug discovery programmes rather than simply a final material-production step.
How Are Peptides Used in Drug Discovery?
Peptides are used at multiple stages of drug discovery, from understanding target biology and identifying active sequences to SAR, optimisation and therapeutic development.
Target Validation and Mechanistic Studies
Peptides help researchers investigate target biology, study molecular interactions and evaluate whether modulating a pathway produces the expected biological response.
These studies can provide evidence supporting target engagement and help investigate the underlying mechanism of action before a programme progresses towards more advanced therapeutic development.
Screening and Hit Identification
Peptide sequences can be systematically varied to investigate their interaction with a biological target.
Researchers may compare:
– Sequence variants
– Truncated sequences
– Amino acid substitutions
– Modified residues
– Linear and constrained structures
– Different conjugation strategies
The resulting data can help identify peptide sequences or structural features associated with desirable biological activity.
What Is Peptide SAR?
Systematic analogue generation allows researchers to establish structure–activity relationships and guide iterative peptide optimisation.
In peptide discovery, SAR studies can involve changing individual amino acids, removing parts of a sequence, introducing modified residues, or altering the overall peptide structure.
The objective is to understand which structural features contribute to properties such as:
– Potency
– Selectivity
– Stability
– Target engagement
– Other desired biological properties
Systematic analogue generation therefore allows researchers to move from an initial peptide sequence towards increasingly optimised molecules.
Protein-Protein Interaction Research
Protein-protein interactions represent an important class of drug discovery targets. Their interfaces can be structurally diverse and may not always contain conventional small-molecule binding pockets.
Peptides and peptide-based approaches provide useful starting points for investigating — and in some cases modulating — these interactions. Nature Reviews Drug Discovery: Protein-protein interactions
Therapeutic Development
Peptide medicines are already established across multiple therapeutic areas, with metabolic and endocrine diseases being particularly prominent examples.
Modern peptide therapeutics also demonstrate how structural engineering can influence pharmacological properties.
For example, tirzepatide is a 39-amino-acid peptide modified with a C20 fatty diacid moiety, illustrating how chemical modification can influence peptide exposure and pharmacokinetic properties. U.S. FDA: Tirzepatide Review
Peptide-Drug Conjugates and Targeted Approaches
Peptides can also form part of more complex therapeutic constructs.
In a peptide–drug conjugate (PDC), a peptide component is chemically linked to a therapeutic payload. Depending on the design, the peptide may contribute target recognition or delivery, while the attached payload provides the intended pharmacological activity.
This extends the use of peptides beyond standalone therapeutics into targeted delivery and other engineered therapeutic approaches.
What Are the Advantages of Peptides in Drug Discovery?
Peptides offer several properties that can be valuable during discovery and optimisation.
Peptide property
1. Target recognition – Can support selective interactions with biological targets
2. Larger interaction surfaces – Can help researchers investigate extended protein interfaces
3. Sequence flexibility – Enables systematic SAR exploration
4. Structural flexibility – Allows different conformations and architectures to be investigated
5. Chemical modification – Enables investigation and optimisation of properties such as stability, exposure and pharmacokinetics
Target Specificity
Peptides can form specific interactions with receptors and proteins, supporting selective target engagement.
Larger Interaction Surfaces
Their size and structure can allow peptides to engage molecular surfaces that may be difficult to address with smaller molecules.
Sequence-Level Optimisation
Researchers can systematically modify peptide sequences through substitution, truncation and analogue generation to establish structure-activity relationships.
Structural and Chemical Flexibility
Approaches such as cyclisation, stapling and incorporation of non-natural amino acids can expand the structural space available for optimisation.
The key value of peptides is therefore not simply their specificity. It is the combination of specific molecular recognition and the ability to iteratively modify the molecule around a biological target.
Peptides vs Small Molecules: What Is the Difference?
Peptides and small molecules offer different approaches to drug discovery.
Small molecules are generally compact and can be well suited to defined binding pockets. Peptides can offer extended molecular interaction surfaces and allow researchers to explore targets through sequence- and structure-based optimisation.
This difference can become particularly relevant when investigating extended protein interfaces or biological targets that may be difficult to address with conventional small molecules.
However, peptides also present challenges that need to be considered during development, including stability, permeability, pharmacokinetics, delivery and manufacturing.
The choice of modality should therefore depend on the target, mechanism, desired pharmacology and development requirements, rather than assuming that peptides or small molecules are universally preferable.
What Are the Key Challenges of Peptide Drug Discovery?
Peptide programmes can face several challenges that need to be considered early in discovery.
Challenge
1. Proteolytic stability – Enzymatic degradation can reduce biological exposure
2. Half-life – Rapid clearance can limit duration of action
3. Permeability – Limited membrane penetration can restrict access to some intracellular targets
4. Oral bioavailability – Gastrointestinal degradation and limited absorption can restrict systemic exposure following oral administration.
5. Manufacturing – Longer, aggregation-prone or highly modified sequences can increase synthesis complexity and may require additional optimisation and purification
6. Delivery – The administration route can influence achievable exposure
Peptide therapeutics can be affected by enzymatic degradation, limited permeability and rapid plasma clearance. These properties can influence both experimental design and eventual therapeutic development. PubMed: Challenges in peptide therapeutics
Proteolytic Stability
Peptides can be susceptible to enzymatic degradation. If a peptide is rapidly broken down, maintaining sufficient biological exposure can become difficult.
Half-Life and Clearance
Rapid clearance can limit the duration for which a peptide remains available at its target.
Permeability
Limited membrane penetration can be an important consideration when the intended target is located inside a cell.
Oral Delivery
Oral peptide delivery presents additional challenges because peptides must withstand the gastrointestinal environment, avoid enzymatic degradation and cross biological barriers before reaching systemic circulation.
Research continues to explore chemical modifications, permeation enhancers, encapsulation and other delivery technologies to address these limitations. PubMed: Strategies for overcoming barriers to oral peptide delivery
For scientists, this means that strong activity in an assay is only one part of peptide optimisation. The molecule also needs properties that support its intended application.
How Are Peptides Optimised to Overcome These Challenges?
Peptide optimisation involves modifying the molecule according to the specific property that needs improvement.
Optimisation approach
1. Cyclisation – Constrain conformation and potentially improve stability
2. Stapling – Stabilise a desired peptide conformation
3. Non-natural amino acids – Expand chemical and structural space
4. PEGylation – Modify pharmacokinetic behaviour
5. Lipidation – Influence exposure and circulation properties
6. Conjugation – Introduce targeting, delivery or other functionality
These approaches allow researchers to move beyond the original sequence and investigate molecules with different biological and physicochemical properties.
Importantly, optimisation is rarely about improving a single property in isolation. A modification that improves stability, for example, may affect permeability, potency, or other characteristics.