ThirdLaw Molecular is developing a new class of therapeutic molecules with potential to address age-related deterioration.
Five years ago, we brought you the story of Temple University spinout ThirdLaw Molecular and its work to develop an entirely new class of compounds called spiroligomer molecules. Back then, the company was focused on demonstrating that its technology could be used to build synthetic diagnostics for its primary investor, the US Department of Defense.
Fast forward to today, and ThirdLaw has made significant progress, recently launching a DNA-encoded library containing 4.5 billion spiroligomer macromolecules. The library allows for rapid and efficient screening against biological targets, potentially accelerating the identification of new therapeutic candidates that the company claims combine the best features of both biologics and small molecules.
Having completed a $1.5 million pre-seed round, ThirdLaw is now raising funding to demonstrate the technology’s efficacy in animal models and is seeking partnerships with pharmaceutical partners to bring these fascinating molecules into clinical trials.
Longevity.Technology: At the heart of ThirdLaw’s innovation is its spiroligomer technology, a novel chemical platform that creates synthetic, modular, fused-ring structures with diverse functional groups. This allows for precise control over molecular shapes, enabling the design of compounds that can selectively bind to proteins of biological interest, including those previously considered “undruggable”. To learn more, we caught up with Dr Christian Schafmeister, ThirdLaw’s founder and president.
Schafmeister, a professor of chemistry at Temple University, founded ThirdLaw in 2020 to capitalize on the potential of spiroligomer-based molecules. He found an eager early backer in the DoD, which has funded the company’s work to the tune of $16.5 million over the past five years, building synthetic diagnostics that could be rapidly developed to address emerging threats, and have the stability to withstand military environments.
Temple University Professor Christian Schafmeister, on his commercialisation in the form of his new start-up – ThirdLaw Technologies for spiroligomers.
Dr Christian Schafmeister is founder and president of ThirdLaw Molecular.
ThirdLaw initially focused on developing DNA-encoded libraries that could screen for molecules binding to dangerous bacteria and viruses, as part of its mission to create an artificial immune system capable of identifying and potentially neutralizing dangerous biological threats.
“We did it – we made an artificial immune system, we made four and a half million of the largest, most complex molecules outside of nature,” says Schafmeister. “Now what we’re doing is transitioning to developing therapeutics – I think we can make therapeutics based on spiroligomer molecules that will change medicine.”
Scaling up for therapeutics
The breakthrough in scaling ThirdLaw’s technology emerged through a critical transition from bead-based to “solution-phase” DNA-encoded libraries. By attaching molecules directly to DNA in solution, ThirdLaw dramatically expanded its molecular library from hundreds of thousands to potentially billions of distinct molecules.
The new method integrated a DNA “tag” directly into the spiroligomer molecular structure, allowing for unique identification of each complex and nuanced molecular design. The innovation involved using four molecular segments in new configurations, creating a more flexible and expansive library. By swapping entire molecular chunks and individual building blocks, ThirdLaw could now create a high-resolution search capability that was previously impossible.
“We went from beads, where we’re squeezing out one search at a time, to this solution-phase library where we can screen against 1,000 targets with a single library,” says Schafmeister. “This is more than just an incremental improvement – it’s a fundamental reimagining of molecular library development. We were able to make four and a half billion different molecules.”
Advantages of spiroligomers
From a therapeutic perspective, Schafmeister says the new spiroligomer molecules developed by ThirdLaw offer several advantages over traditional drug development approaches, particularly their highly complex structures, which allow them to selectively target disease-related proteins.
“Unlike small molecule drugs that fit into protein ‘pockets,’ spiroligomer molecules can bind to protein surfaces with high specificity, much like a lock and key mechanism,” he explains. “They have the potential to overcome the limitations of both traditional small molecules and biologics, combining the high selectivity typically associated with biologics with the favorable drug-like properties of small molecules, including cell permeability, oral bioavailability, protease resistance, and scalable synthesis.”
Crucially, the size of spiroligomer molecules is uniquely positioned between small molecules and large biologics like enzymes or antibodies.
“At approximately 5,000 Daltons, our molecules are about 5% the size of a typical enzyme, allowing them to penetrate tight cellular spaces where conventional drugs cannot reach,” explains Schafmeister. “This enables them to interact with targets that were previously inaccessible, and therefore potentially treat diseases previously considered undruggable.”
Unlike peptides or protein-based therapeutics, spiroligomer molecules are ignored by our biology. This means they can persist in the body much longer without being immediately broken down. While comparable peptide-based drugs might have a half-life of just a minute or two, spiroligomer molecules can remain intact for extended periods.
“They are completely unrecognized by natural enzymes and proteases, so they’re not going to get chewed up in the body,” says Schafmeister. “They persist for a long time, while other molecules get chewed up within minutes.”
According to ThirdLaw, spiroligomer molecules are orally available, well-tolerated in initial mouse studies, and can distribute effectively between blood and tissue. They do not raise immune responses like artificial enzymes would, making them potentially safer and more versatile than current therapeutic approaches. Critically, they also demonstrate remarkable cell permeability, diffusing into cells rapidly, which is unheard of in molecules of their size.
“They diffuse into cells within 20 minutes by passive diffusion – bam, and they’re in!” says Schafmeister. “They act like small molecules, even though they’re three to five times bigger.”
Potential longevity applications
From a longevity perspective, Schafmeister envisions spiroligomer molecules as “the smallest surgeons imaginable” – molecules that can recognize specific chemical damage, enter the body, fix that precise damage, and then be cleared through the kidneys without causing broader systemic effects. He suggests this approach could one day revolutionize treatment for age-related chemical damages, providing a mechanism to periodically “tune up” the body by removing accumulated molecular damage.
ThirdLaw is exploring the potential to address glucosepane cross-links – the complex molecular bonds that accumulate in tissues and contribute to aging-related deterioration. Schafmeister plans to synthesize these cross-links and then screen his molecular library to identify potential cross-link breakers. The ultimate goal is to develop catalysts that can break these molecular bonds, which he says would represent a major breakthrough in directly addressing one of the most challenging aspects of molecular aging.
The potential applications of spiroligomer technology are vast, and ThirdLaw is also exploring its use in developing next-generation cancer therapies, anti-inflammatory drugs, and other therapeutics, as well as creating new tools for pathogen diagnostics. To harness the potential of the technology, the company is opening its doors for collaboration with pharmaceutical companies.
“We have been talking to one large pharma company for the last year, and we’re hopefully working towards a strategic partnership there,” says Schafmeister. “Of course, the pharmaceutical industry is very conservative and very risk averse, so when you come in with a new technology like spiroligomer compounds, it can take some time to get their buy-in!”
To support the next phase of its journey, ThirdLaw is now aiming to raise an additional $7 million in venture funding.
“We’re trying to build something here, and $7 million would get us to demonstrating that these molecules can work in animals,” says Schafmeister. “And to allow us to do the pre-clinical work to show that these molecules can make highly effective, and, above all, safe medicines.”
Images courtesy of ThirdLaw Molecular.