Key Takeaways
- •Recent developments in drug discovery highlight a growing convergence between G protein-coupled receptor (GPCR) biology and radioligand therapies, with functional peptide screening platforms emerging as a key technical differentiator.
- •GPCRs have long been a cornerstone of drug development.
- •“GPCRs have always been a major focus for drug discovery, and even more so with the advent of drugs targeting GLP-1R and other incretin receptors,” says Simon Bushell, External Innovation and Business Development lead at Orbit Discovery.
Functional Peptide Screening Gains Traction in GPCR and Radiopharmaceutical Development
Recent developments in drug discovery highlight a growing convergence between G protein-coupled receptor (GPCR) biology and radioligand therapies, with functional peptide screening platforms emerging as a key technical differentiator. As pharmaceutical companies and contract research organizations invest heavily in high-throughput methods that go beyond simple binding assays, the field is moving toward more sophisticated approaches that can identify peptides capable of activating receptors rather than merely attaching to them.
GPCR Renaissance and Orphan Receptors
GPCRs have long been a cornerstone of drug development. These seven-transmembrane proteins sit on cell membranes and control a vast array of signaling pathways, making them biologically central to human physiology. They already account for a large share of approved drug targets, so the pharmaceutical industry knows they are druggable. Yet many GPCRs remain underexplored, especially orphan receptors whose natural ligands are unknown. This leaves a significant discovery opportunity for new ligands and new mechanisms of action.
“GPCRs have always been a major focus for drug discovery, and even more so with the advent of drugs targeting GLP-1R and other incretin receptors,” says Simon Bushell, External Innovation and Business Development lead at Orbit Discovery. These molecules target receptors such as the glucagon-like peptide-1 receptor (GLP-1R), which is a class B GPCR and relevant in the treatment of metabolic diseases.
Renewed interest in GPCR biology is drawing attention to functional peptide screening platforms. In a crowded AI drug discovery market, functional peptide screening could be a real differentiator. Several biotechs are already targeting GPCRs, including Septerna, Structure Therapeutics, and Escient Pharmaceuticals. The space is attracting significant capital, as evidenced by Eli Lilly’s July 2024 deal with Radionetics Oncology. Lilly made a $140 million upfront payment and secured the exclusive future right to acquire the biotech for $1 billion. According to a press release, the deal gave Eli Lilly “access to novel GPCR targets.”
Radiopharmaceuticals and Peptide-Mediated Targeting
Radiopharmaceuticals represent another hot area for investigation. A ligand is a molecule that binds to the GPCR receptor, and in radiopharma that ligand serves as the targeting component of a radioactive drug. As BioSpace previously reported, radiotherapeutics is a field ripe for exploration, with enormous potential due to the multiplicity of cancer surface targets that can be addressed with different carriers, isotopes, and formulation methods.
Contract research organizations are actively engaged in functional screening for GPCR agonists and peptide-mediated targeting relevant to radioligand therapies. Orbit Discovery has partnered with a range of emerging biotechs and Big Pharma to identify new peptides that modulate inflammation and to develop targeting peptides that direct treatments to specific cancers and across the blood-brain barrier. The company’s discovery platform also identifies highly differentiated peptides as treatments for pain relief and other neurological conditions.
The intersection of GPCR targeting and radiopharmaceuticals is particularly promising because many GPCRs are overexpressed on cancer cells. By developing peptide ligands that selectively bind those receptors and then carrying a radioisotope, researchers can deliver cytotoxic radiation directly to tumor sites while sparing healthy tissue. This approach requires not just binding specificity but also the ability to trigger internalization of the receptor-ligand complex, which is where functional screening can provide an advantage.
Functional Screening Versus Binding-Only Approaches
Most peptide screening methodologies focus strictly on target binding as a readout. This approach works well for finding targeting peptides for therapeutic delivery or for inhibiting protein-protein interactions. However, binding-based methods struggle to identify peptide agonists: peptides that not only bind a target but also induce the conformational changes necessary to activate it. Bushell explains that this limitation is significant, especially for GPCRs where activation depends on the receptor changing shape to couple with intracellular G proteins.
Functional peptide screening platforms address this gap by using cell-based assays that measure actual signaling events, such as calcium flux, cyclic AMP accumulation, or beta-arrestin recruitment. High-throughput versions of these assays can screen very large peptide libraries directly against living cells, using functional readouts to identify novel agonists that activate signaling pathways. This approach gives pharmaceutical companies accurate hits that help derisk programs and speed translation, making these platforms a sensible differentiator in an otherwise crowded AI drug discovery landscape.
Other service providers in the GPCR discovery market include Charnwood Discovery, Creative Bioarray, and Creative Biogene. The global peptide library screening services market is poised for significant growth and was projected to reach $50 billion last year. According to a Data Insights market report: “Peptide libraries offer a powerful tool for identifying lead compounds with therapeutic potential, enabling researchers to screen vast numbers of peptides efficiently. The continuous innovation in peptide synthesis and high-throughput screening platforms also plays a crucial role in expanding the capabilities and applications of these services.”
Clinical Translation and Scientific Context
The shift toward functional screening reflects a broader trend in drug discovery: moving from static binding assays to dynamic, biology-driven readouts. For GPCRs, this is especially important because many drugs fail not because they don’t bind but because they activate unintended signaling pathways or fail to produce the desired functional outcome. Functional screening can identify biased agonists that selectively activate certain downstream pathways while avoiding others, potentially reducing side effects.
In the radiopharmaceutical space, functional screening can help identify ligands that are efficiently internalized by target cells, maximizing radiation dose delivery. The ability to screen against live cells also captures complexities such as receptor density, membrane environment, and co-receptor interactions that cannot be replicated in purified protein assays.
Orbit’s platform exemplifies this integrated approach. By screening against cells and using functional readouts, it can find peptides that not only bind to GPCRs but also trigger the right conformational changes. This dual capability is particularly valuable for radioligand therapies, where the peptide must both recognize the target and facilitate uptake of the radioisotope into cancer cells.
Looking ahead, the combination of AI-driven library design with functional screening could further accelerate discovery. While AI can predict binding affinities and generate virtual peptide libraries, functional screening remains essential to validate that those libraries actually work in biological systems. The two approaches are complementary rather than competitive, and the most successful platforms will likely integrate both computational predictions and high-throughput functional assays.
Frequently Asked Questions
Q: What is the main advantage of functional peptide screening over binding-based screening for GPCRs?
A: Binding-based screening can identify peptides that attach to a GPCR, but functional screening goes further by measuring whether the peptide actually activates the receptor and induces the necessary conformational changes for signaling. This is critical for finding agonists that trigger therapeutic responses rather than merely blocking the receptor.
Q: How are GPCRs relevant to radiopharmaceutical therapies?
A: Many GPCRs are overexpressed on cancer cell surfaces. By developing peptide ligands that bind to these receptors and carry a radioisotope, researchers can deliver radiation specifically to tumor cells. Functional screening helps identify ligands that not only bind but also cause internalization of the receptor, which improves the therapeutic payload delivery.
Q: Why are orphan GPCRs considered a discovery opportunity?
A: Orphan GPCRs are receptors whose natural ligands are not yet known. Because they are structurally druggable but functionally unexplored, they represent a pool of potential new targets for treating diseases where existing drugs are ineffective. Functional screening can help identify synthetic peptide ligands that activate these receptors.
Q: What role does the Eli Lilly/Radionetics deal play in the GPCR screening market?
A: The deal, involving a $140 million upfront payment and a future option to acquire Radionetics for $1 billion, signals strong pharmaceutical interest in novel GPCR targets. It validates the commercial potential of GPCR-targeted peptide discovery and has encouraged other companies and CROs to invest in functional screening platforms.