Meet the Goldilocks Molecules

Currently, approximately 800 proteins are accessible to conventional small molecule therapeutics, but biological therapeutics such as monoclonal antibodies can only target the roughly 10 percent of proteins that are outside of cells. Thus, 90 percent of proteins are considered “undruggable” by existing treatments. Small molecules are often not selective because of their size, leading to off-target effects. Biologics, however, are huge by comparison and more selective, with fewer off-target effects, but are not orally bioavailable and so must be administered by injection.  

With support from the US Department of Defense whilst a researcher at Temple University, Philadelphia, ThirdLaw Molecular (TLM) founder and president Christian Schafmeister was tasked with developing technologies for detecting and neutralizing biological and chemical agents for the military. TLM was founded in 2020 so he could progress his research, as well as explore the far-reaching applications of Spiroligomer molecules. Derived from “spiral” and “oligomer”, these are intermediate in size and combine the drug-like properties of small molecules, such as cell permeability and oral bioavailability, with the high selectivity for target proteins that is seen with biologics. The company nicknames them “Goldilocks molecules.” We spoke with Schafmeister to learn more.  

Why are they nicknamed “Goldilocks molecules”? 
 

They are in-between the size of small molecules and biologics. Spiroligomer molecules are complex, fused-ring structures that are approximately 2-10 times the size of conventional small molecules. When we link these together as macromolecules, we can form structures that are 4,000-5,000 Daltons in size – the approximate size of an antibody binding site. The in-between size of these molecules, which have lengths, shapes and functional groups attached that can all be pre-programmed, enables the design of molecules that are tailored to bind to the protein surfaces, where they are highly selective with few off-target effects. The key feature of Spiroligomers that differentiates them from other molecules is the ability to fuse multiple rings together, creating shapes that are tailored to bind their targets.  

Can you tell us a bit about the history of what inspired the development of Spiroligomers and how you created them?
 

As a graduate student, I developed the first artificial protein called 4HB1 and demonstrated that it had the three-dimensional structure I designed it to have. This took me four years and I was very frustrated at the difficulty of controlling the shape of proteins because of the difficulty of working with the unsolvable process of protein folding. The fundamental challenge is that proteins are made of amino acids linked by single bonds that allow each amino acid to twist and rotate relative to the next – making it very difficult how to predict and control how they fold into specific shapes.

I imagined another way to eliminate folding by connecting building blocks through pairs of bonds to form a ring. If the building blocks were rings, joining multiple building blocks together would result in the molecules representing fused rings, like ladders. I looked at natural molecules that aren’t proteins and this fused-rings motif is very pervasive in the natural molecules that organisms create to control and kill each other. From steroids to the most active marine toxins, such as brevetoxin and maitotoxin, this idea of fused rings is the most powerful way to join atoms together into a molecule that has the highest affinity for the target that it evolved to bind.   

By creating fused ring molecules that are locked into the shape that best matches the protein surface they evolved to bind, nature makes molecules that don’t need to freeze out motion when they bind. They are “pre-organized” to bind their target. This is the idea behind Spiroligomer molecules.  

What were the major challenges in developing the molecules?
 

Fused-ring chemical structures are the basis of some of the most active molecules found in nature, such as estrogen, testosterone, and the highly potent marine toxins brevetoxin and maitotoxin, but they have been incredibly difficult to synthesize – involving as many as 90 synthetic steps. As such, they have remained largely unexplored in medicine. 

As individual Spiroligomer compounds advance into development and commercialization, the general obstacles, supply chain disruption, scaling of processes, compliance with FDA requirements, that may confront any pharmaceutical compound will need to be considered, but these are not expected to be any more challenging for Spiroligomer molecules than with other synthetic compounds.  

How will partnerships help overcome these?
 

In addition to its own internal development, TLM is pursuing partnerships to screen its libraries against biologic targets, validate and optimize hits, and license lead compounds for development and commercialization. The main purpose of this partnership strategy is to work with experts in diverse therapeutic categories to maximize the reach of this technology to address unmet medical needs as quickly as possible.  

What manufacturing advantages do you anticipate?
 

Much of the research has been dedicated to dramatically simplifying the manufacturing process for Spiroligomer molecules such that intermediate building blocks are synthesized in quantity, and then snapped together like molecular Lego, to produce specific Spiroligomer molecules. This process is completed by robots so that molecules can be designed, synthesized, and optimized quickly and efficiently – a methodology we have been using successfully for four years.  

What does success through Spiroligomer molecules look like?
 

This platform offers a huge range of therapeutic applications. Spiroligomer-based molecules can be developed as direct acting therapeutics (agonists, antagonists, allosteric modulators), Spiroligomer-radioisotope conjugates for targeted cancer therapy, or Spiroligomer-drug conjugates for targeted therapeutics. The near-term goal is to prove the concept of the technology with a select number of biologic targets. Ultimately, the mission is to create a revolutionary category of molecules that transform how diseases are diagnosed and treated – more safely and effectively.