In the genomic era, we have identified hundreds of receptors whose functions remain unknown. These "orphan receptors"—proteins with no known natural binding partners—represent a large, untapped pool of potential therapeutic targets. Finding the ligands that activate or inhibit these receptors is a crucial first step in understanding their biology and unlocking their potential for drug discovery. This process, known as receptor deorphanization, is notoriously challenging using traditional methods. Creative Biolabs' phage display screening service for orphan receptor ligands offers a reliable, high-throughput solution to this challenge. We employ advanced membrane protein phage display technology to screen billions of potential ligands against your orphan target. This method enables us to identify specific peptides or protein fragments that bind to the receptor, thereby clarifying its function and supporting drug development. Our platform provides a straightforward way to discover targets and functional ligands that traditional methods often overlook.
This specialized service is a key component of our comprehensive Phage Display Protein Interaction Mapping Service, applying our deep expertise in protein interactions to the challenging frontier of receptor biology.
Receptors on the cell surface are the gatekeepers of cellular communication. They receive chemical signals from the outside world and transmit them into the cell, triggering specific signaling pathways. The G-protein coupled receptor (GPCR) family is the largest and most diverse group of these membrane proteins. They control everything from vision and smell to immune response and mood regulation. Due to their central role in human physiology, GPCRs are the target of approximately 34% of all FDA-approved medications. However, a significant number of identified GPCRs are still "orphans." We know they exist in the genome, and we can observe that they are expressed in tissues; however, we do not know what activates them. Without a known ligand, we cannot trigger the receptor to study its function, and we cannot easily develop drugs to modulate it. The challenge in receptor deorphanization lies in the proteins themselves:
Fig.1 Orphan GPCRs in neurodegenerative disorders.1
Phage display offers a powerful alternative. Instead of guessing which molecule might bind, we can physically test billions of peptides displayed on the surface of a bacteriophage. This allows us to perform an unbiased search for binders against the receptor in its native state, effectively fishing for the missing key that unlocks orphan receptor signaling.
We have developed a suite of specialized screening strategies designed specifically for membrane proteins and orphan receptors. Our goal is to help you characterize your target from the outside in, providing tools that drive functional understanding.
This is our primary service for receptor deorphanization. We screen high-diversity peptide libraries or cDNA libraries against the extracellular domains of your orphan receptor to find natural or synthetic ligands that bind to the receptor surface. These binders act as essential "surrogate ligands," enabling you to activate the receptor in functional assays, map downstream signaling pathways, and set up competitive displacement assays for small molecule drug discovery.
Receptors do not function in isolation; they transmit signals by recruiting specific proteins inside the cell. To map this GPCR interactome, we screen the intracellular loops or C-terminal domains of your receptor against a library of cytoplasmic proteins. This process enables us to identify downstream targets, revealing which G-proteins, arrestins, or kinases physically interact with the receptor tail to propagate the signal.
We follow a rigorous, stepwise process to ensure the discovery of biologically relevant ligands for your orphan target.
Success starts with strategy. We consult with your team to understand the biology of your orphan receptor. The most critical step is the target preparation. Since receptors are membrane proteins, they must be handled with care. We design the optimal strategy, which may involve expressing the receptor in mammalian cells or using virus-like particles (VLPs) to ensure the protein maintains its native fold and active binding sites.
We select the library that best fits your scientific question. To find peptide agonists, we use our high-diversity peptide libraries. To discover targets from the host proteome, we use a cDNA library. We then execute our library screening and biopanning protocols.
Traditional picking of a few phage clones is insufficient for orphan receptor discovery. We employ next-generation sequencing (NGS) to sequence the entire pool of eluted phages. This enables us to detect millions of sequences, providing a comprehensive view of the enriched population. This high sensitivity is crucial for finding ligands that may bind with moderate affinity but high specificity.
Our bioinformatics experts analyze the NGS data to cut through the noise. We seek consensus motifs, characterized by patterns of amino acids that frequently appear in the enriched pool. We align these sequences against biological databases to identify potential natural ligands. This analysis is essential for filtering out "false positives" and identifying true candidates for receptor deorphanization.
We deliver a detailed report containing the ranked list of hit sequences, enrichment factors, and bioinformatics predictions.
To ensure the highest probability of success for your orphan receptor project, we leverage a consolidated technology stack that combines versatile screening environments with our massive library resources.
Orphan receptors are not dead ends; they are new beginnings. Identifying the ligand is the key that unlocks the potential of a mysterious protein as a valuable drug target. Our phage display screening service provides the technology and expertise to perform this receptor deorphanization efficiently and reliably. Let us help you define the undefined. today to discuss your orphan receptor project and receive a custom proposal.
Why is phage display better than traditional high-throughput screening (HTS) for orphan receptors?
Traditional HTS requires a functional assay to determine if a compound is effective. But if you don't know the natural ligand, you don't have a positive control to set up the assay. Phage display is an affinity-based screen. We select for binding first. Once we find a binder, you can use that peptide as a tool to build the functional assay.
Can you work with receptors that are unstable when purified?
Yes. This is a primary strength of our platform. We do not need to purify the receptor if it is unstable. We can perform in vitro cell-based phage display screening using live cells that overexpress your target. By using rigorous subtractive screening, we can target the receptor in its native, stable environment within the cell membrane.
Does this service only find ligands, or can it find downstream signaling partners?
We can do both. To find ligands (agonists/antagonists), we screen against the extracellular domains of the receptor. To discover downstream targets and map the GPCR interactome, we screen against the intracellular domains or loops of the receptor. This allows us to identify the cytoplasmic proteins (like G-proteins or scaffold proteins) that physically interact with your receptor to propagate the signal.
Should I use a Peptide Library or an Antibody Library for my orphan receptor project?
The choice depends entirely on your final goal. If you're aiming to discover a "surrogate ligand" to activate the receptor and study its signaling, a peptide library is the best option because peptides can easily mimic natural ligands to induce conformational changes. If your goal is to stabilize the receptor for structural biology (such as crystallography) or to block its activity (antagonist) for therapeutic purposes, an antibody library is usually more suitable due to the high affinity and stability of these molecules.
How long does a typical orphan receptor screening project take?
Phage display is much faster than traditional methods, such as high-throughput small molecule screening, which can take months or years to set up for orphans. A typical screening project from target preparation and library selection to the delivery of ranked NGS hits usually takes about 6-10 weeks. Optional downstream validation services, like peptide synthesis and biochemical characterization, will add extra time depending on the scope of validation needed.
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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.
