Tackling Previously “Undruggable” Proteins

Currently, only ~800 proteins are accessible to conventional small-molecule therapeutics, while biologic therapies –  such as monoclonal antibodies (mAbs) – can only target approximately 10% of proteins as their size limits them to interacting with proteins on the outside of cells. This leaves 90% of proteins effectively “undruggable” by existing treatment approaches.

While small molecules are orally bioavailable and can penetrate cells, their small size often results in promiscuous binding, leading to off-target effects and potential toxicity. Biologics are highly selective, very large molecules that minimize off-target effects, but are not orally bioavailable, requiring administration by injection. They are also relatively complex and expensive to manufacture, often requiring cold storage conditions.

To bridge the gap, we have developed and patented Spiroligomer molecules, an innovative class of synthetic therapeutics that are intermediate in size between small molecules and biologics.

The key feature of Spiroligomer molecules that differentiate them from other therapeutics is that they are complex, fused-ring structures with lengths, shapes and functional groups attached that can all be pre-programmed. This enables us to design molecules that are tailored to fit specific protein surfaces, helping to achieve high selectivity with fewer off-target effects.

These molecules combine the best attributes of both small molecules and biologics, offering cell permeability and oral bioavailability similar to small molecules while maintaining the high target selectivity of biologics. They also have the potential to address “undruggable” proteins, expanding the therapeutic landscape.

Spiroligomers are a promising class of synthetic molecules that are particularly well-suited for tackling previously undruggable targets, such as protein–protein interactions (PPIs) inside of cells and stabilizing intrinsically disordered proteins (IDPs).

Spiroligomer molecules address undruggable targets by:

1. Accessing protein surfaces or shallow grooves on protein surfaces

Small molecule drugs don’t display enough surface area to bind exterior protein surfaces. This is why they presently only target about 800 proteins in the human genome.

Synthesizing larger organic molecules almost always adds more flexibility, adding more rotatable bonds. This flexibility must be “frozen out” when binding a target protein, and so larger floppy molecules also have trouble binding proteins.

The rigid polycyclic, expandable backbone of Spiroligomer molecules provides structure and large, programmable surfaces to bind protein surfaces. Natural products are replete with fused-ring molecules, from steroids to the most awesome and active non-protein molecules in nature, like brevetoxin and maitotoxin.

To develop drugs, you need to be able to make lots of molecules to discover the ones that selectively bind their target. Fused ring molecules are hard to synthesize; brevetoxin takes 90 steps.

2. Disrupting PPIs

Many PPIs are considered 'undruggable' because traditional small molecules lack sufficient structured binding surfaces to stick to protein surfaces and effectively disrupt interactions between proteins involved in disease. Antibodies can’t target these undruggable interactions because they can’t access the interior of cells. Spiroligomer molecules can be designed to precisely fit across large, complex binding interfaces, making lots of interactions with the protein surface from a pre-organized scaffold that doesn’t pay an entropic penalty when it binds the surface.

We have observed that 80% of Spiroligomer molecules penetrate cells by passive diffusion. Within Spiroligomer molecules, we carefully limit the N-H hydrogen bond donors that make it difficult for other molecules – like peptides – to cross cell membranes. In the early 2000’s, Daniel Veber and co-workers’ analysis of molecular properties that influence oral bioavailability of drug candidates demonstrated that higher preorganization correlates with higher bioavailability.

This opens the potential to target proteins like β-catenin, MDM2, p53, Myc and transcription factors involved in cancer and other diseases.

3. Binding IDPs

IDPs, such as c-Myc and tau, lack stable structures and deep pockets, making them intractable to target with small molecules. The modular and programmable structures of Spiroligomer molecules allow them to create structured surfaces that match the folded conformation of these flexible proteins, binding and stabilizing transient conformations and controlling their function.

4. High specificity and tunability

Unlike small molecules, Spiroligomer molecules can be designed with high specificity. This will reduce promiscuity and toxicity and improve the drug's selectivity for its intended target.

5. Enhanced stability and bioavailability

Compared to peptides, Spiroligomer molecules are unrecognized by proteases, increasing their half-life in the body. Their synthetic nature allows for optimization of solubility, permeability and metabolic stability, making them suitable for oral or injectable administration.

Spiroligomer molecules hold immense potential in cancer therapy, particularly for targeting p53 mutations, one of the most common and challenging mutations in human cancers. This is thanks to their ability to disrupt PPIs, stabilize mutant proteins and engage previously undruggable targets.

Small molecules often fail due to off-target toxicity, metabolic instability or rapid degradation. Peptide-based drugs, such as stapled peptides –  a technology that I co-invented – have improved specificity, but face delivery challenges and poor oral bioavailability.

Spiroligomer molecules combine the best of both worlds, offering:

• Highly programmable, complex structures with precise three-dimensional control for high-affinity binding.
• Enzymatic stability for longer duration of action.
• Potential oral bioavailability, unlike many biologics.

The convenient, modular synthesis of Spiroligomer molecules allows us to:

• Create enormous DNA-encoded libraries of Spiroligomer molecules for screening against mutant forms of p53 after removing library members that bind wild-type p53.
• Rapidly synthesize many variants of Spiroligomer molecules to optimize them for binding to mutant target proteins in a medicinal chemistry program.

The ability of Spiroligomer molecules to selectively bind proteins with high affinity and specificity makes them ideal candidates for next-generation diagnostic tools. They are rugged molecules that don’t require a cold chain to maintain their structure and don’t denature over time like antibodies do. Their unique structural properties allow them to outperform traditional antibodies and small-molecule probes in various applications, from early disease detection to biomarker quantification and imaging.

1. Ultra-sensitive biomarker detection

Many diseases, including cancer and neurodegenerative disorders, require early and precise biomarker detection, but traditional methods (e.g., ELISA and/ or lateral flow assays) can lack sensitivity and stability.

The rigid, programmable structures of Spiroligomer molecules allow them to be designed for high-affinity binding to disease-specific proteins.

Compared to antibodies, Spiroligomer molecules resist degradation, function in harsh environments and can be synthesized with perfect quality control. Due to their smaller size, they can also access surfaces on target proteins that antibodies cannot.

Example: Detecting low-abundance cancer biomarkers (e.g., p53 mutants, HER2, or PD-L1) in liquid biopsies with greater sensitivity.

2. Real-time, in vivo imaging for disease monitoring

Existing imaging agents (e.g., antibodies or nanoparticles) can have poor tissue penetration, off-target binding or slow clearance.

The small size and tunable chemistry of Spiroligomer molecules allows them to penetrate tissues more effectively than bulky antibodies. The molecules can also be labeled with fluorescent, radioactive, or PET tracers for real-time imaging of disease progression.

Potential applications:

• Cancer imaging: Selectively binding tumor-specific proteins (e.g., integrins, EGFR or mutant KRAS) for PET or fluorescence imaging.
• Neuroimaging: Detecting amyloid-beta or tau proteins in Alzheimer’s disease with better resolution than current PET tracers.

Spiroligomer technology is opening new frontiers across drug discovery, diagnostics and biomaterials, but some of the most exciting emerging applications include:

Targeting “undruggable” proteins in cancer:

Many diseases are driven by proteins that lack conventional drug-binding pockets, such as mutant p53, KRAS and β-catenin

How Spiroligomer molecules help:

• Their rigid, programmable structures allow them to selectively bind and stabilize or disrupt these challenging proteins.
• They could reactivate tumor suppressors like p53, disrupt oncogenic (PPIs) or block toxic protein aggregates in neurodegeneration.
• Spiroligomer molecules designed to target tau or amyloid-beta could lead to disease-modifying therapies

Next-generation antiviral therapies (beyond mAbs)

Traditional antiviral drugs often struggle with viral mutations and drug resistance.

How Spiroligomer molecules help:

• They can block viral entry into cells by mimicking host cell receptors (e.g., for HIV, influenza or SARS-CoV-2).
• Unlike mAbs, Spiroligomer™ molecules aren’t easily degraded and can be synthesized at scale.
• Spiroligomer molecules penetrate cells and have demonstrated oral availability.
• A Spiroligomer-based antiviral could provide broad-spectrum protection against evolving viruses–a potential game-changer for pandemic preparedness.

Smart biomaterials and drug delivery systems

Traditional drug carriers (e.g., liposomes and polymer nanoparticles) can struggle with targeted delivery and controlled release.

How Spiroligomer molecules help:

• Their tunable backbone and chemical flexibility allow them to self-assemble into smart drug delivery vehicles.
• They can be designed to release drugs in response to specific cellular or environmental triggers (e.g., pH changes in tumors).
• Spiroligomer-coated nanoparticles could cross the blood-brain barrier  to deliver drugs for glioblastoma or Parkinson’s disease.