Cells communicate by sending and receiving signals that are mediated through receptors. The compounds that bind to and modulate these receptors, agonists and antagonists, are central to normal physiology, disease pathogenesis, and modern drug discovery/therapeutic development. Novel and highly selective receptor modulators are key therapeutic targets across the pharmaceutical industry. The main reason for discovery campaign failures lies in the scarcity of functional binders rather than just binders. The reality for complex receptor systems is that you may need:
Our service can fulfill all three needs. The team at Creative Biolabs employs advanced screening technology, a key part of our broader Functional Phage Display Screening Services, to assist researchers in finding high-affinity receptor agonists and antagonists. This approach provides the necessary tools for exploring intricate biological pathways and advancing therapeutic development.
| What We Do | Our Approach |
|---|---|
| Target & Strategy Design | We work with you to plan the best screening strategy, deciding whether to use purified proteins or whole cells to find the ideal binder. |
| Library Selection | We screen vast phage libraries against your target to find the best matches, using negative selections to remove non-specific binders. |
| Functional Triage | We test the initial "hits" in relevant cell-based assays to confirm they have the specific biological function you need. |
| Hit Recovery & Sequencing | We rapidly sequence the best binding clones using NGS and bioinformatics to identify unique and promising candidates. |
| Recombinant Reformats | We convert the selected binders into user-friendly formats, such as full-length antibodies (IgG), Fabs, or synthetic peptides, for your downstream use. |
| Characterization | We measure key properties of the final candidates, such as their binding strength (affinity), specificity, and how they interact with other molecules. |
| Optional Engineering | We can further optimize your best candidates by fine-tuning their binding, improving their stability, or engineering them for enhanced function. |
Cell surface and intracellular receptors are central to virtually all physiological processes, including growth, differentiation, metabolism, and neurotransmission. Their function is tightly regulated by ligands, which can be broadly categorized into two classes:
The delicate balance between agonist and antagonist signaling is vital for homeostasis. When this balance is disrupted, it can lead to a wide range of diseases, including cancer, autoimmune disorders, metabolic syndromes, and neurological conditions. Therefore, the ability to identify and develop specific receptor agonist and antagonist molecules is of immense therapeutic value.
Phage display screening is a Nobel Prize-winning technology that has revolutionized the discovery of high-affinity binding molecules, including antibodies, peptides, and other protein scaffolds. The technique utilizes bacteriophages to display vast libraries of proteins—often billions or trillions of unique variants—on their surfaces. The core principle is the physical linkage between the displayed protein (phenotype) and the gene encoding it (genotype), which is contained within the phage particle. This connection enables a robust selection process known as biopanning.
The process of phage display library screening involves a series of iterative cycles designed to enrich the library for phages that display proteins binding to a specific target.
This cycle is typically repeated 3-5 times, with each round progressively enriching the phage pool with binders that have high affinity and specificity for the target receptor.
While standard biopanning is excellent for identifying binders, discovering functional molecules, such as receptor agonists and antagonists, requires a more sophisticated approach. The screening strategy must be designed not just to find binders, but to differentiate between molecules that modulate receptor function and those that are merely inert binders. At Creative Biolabs, our screening workflows are intelligently designed to isolate molecules with desired functional outcomes.
For antagonist discovery, our phage display screening is engineered to isolate binders that directly block the native ligand's binding site or allosterically prevent receptor activation. We employ a multi-step strategy using our diverse peptide or antibody libraries. The process begins with adverse selection against irrelevant targets to eliminate non-specific binders. Subsequently, iterative rounds of biopanning are performed with increasing wash stringency to enrich for high-affinity clones with slow off-rates. Crucially, we utilize competitive elution with the receptor's natural ligand, a powerful method that specifically isolates phages occupying the functionally critical epitope. Hits are then advanced to a functional validation cascade, including ligand-competition binding assays and cell-based reporter assays, to confirm their inhibitory activity. This robust workflow delivers a highly vetted panel of receptor antagonist candidates, characterized by their potency and specificity for your research applications.
Discovering receptor agonists requires a nuanced approach, and our phage display antibody screening is tailored to identify molecules that either stabilize the receptor's active conformation or induce receptor clustering to initiate signaling. We perform selections on physiologically relevant targets, such as cells overexpressing the receptor in its native membrane environment. A key strategy involves conformation-specific biopanning: we conduct negative depletion against the receptor in its inactive state, followed by positive selection on the receptor stabilized in its active conformation. This enriches for binders that recognize the functionally active form. Following enrichment, individual clones are rapidly reformatted and evaluated in primary functional screens to confirm their agonist activity. This methodology efficiently filters out non-functional binders, yielding a qualified list of full or partial receptor agonist leads ready for your downstream studies.
| Antagonist Screening | Agonist Screening | |
|---|---|---|
| Primary Goal | Isolate binders that block agonist function. | Isolate binders that activate the receptor. |
| Key Strategy | Competitive elution using a known agonist. | Confirmation-specific screening or functional elution. |
| Elution Method | Displacement with a natural ligand. | Often involves harsher elution or specialized cell-based methods. |
| Complexity | Generally, more straightforward. | Technically more challenging; requires sophisticated assay design. |
| Validation | Confirmed by blocking a known agonist's effect in a functional assay. | Confirmed by directly inducing a signal in a functional assay. |
The success of a phage display screening campaign depends critically on the quality and diversity of the library. Creative Biolabs offers a comprehensive suite of pre-made and custom libraries to suit a wide range of projects.
We are specific in our service that phage display antibody screening, as well as phage display library screening, workflows are geared towards the production of actionable receptor agonist antagonist leads. In our experience, some programs require a mixed panel of agonist and antagonist candidates. In contrast, others have a more singular focus on orthosteric antagonist blockers or allosteric agonists that bias signaling output. The strategies detailed previously work to achieve all of these objectives in an effective phage display screening system.
Identification of novel receptor agonists and antagonists is a significant goal in both basic biomedical research and drug discovery. Phage display screening is a powerful, fast, and highly effective technology to address this need. Delivering immense molecular diversity to a target receptor in a selectable format enables the rapid identification of highly potent and selective modulators with the potential to open new therapeutic opportunities. Collaborate with Creative Biolabs and our world-class phage display screening platform to rapidly identify new modulators for your target. We can help you advance your research and discover the next generation of functional molecules to understand biology and fight disease. to discuss your project with our experts!
Phage display is a powerful method for discovering new peptide-based drugs, including agonists and antagonists. A 2018 study provides an excellent example of this technique in action. The researchers' goal was to identify a single peptide that could activate two distinct receptors: the glucagon receptor (GCGR) and the GLP-1 receptor (GLP1R), which are key targets for the treatment of diabetes and obesity. To do this, they first created a special phage display library based on the glucagon protein sequence. Figure 1 shows how they designed this library by creating five sub-libraries with variations in specific regions. Next, they used this library in a multi-step screening process. They screened the phages by alternating between two types of cells: one expressing GCGR and the other expressing GLP1R. The two different screening plans they used are outlined in Figure 2. This strategy was highly successful, leading to the discovery of many new and potent peptide co-agonists that worked on both receptors. This study clearly demonstrates that phage display screening is a highly effective and reliable method for identifying new peptide agonists for key therapeutic targets.
Fig.1 Phage display library construction.
Fig.2 Panning strategy for dual GCGR/GLP1R binders.
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Please kindly note that our services can only be used to support research purposes (Not for clinical use).
Creative Biolabs is a globally recognized phage company. Creative Biolabs is committed to providing researchers with the most reliable service and the most competitive price.
