DoD-funded ThirdLaw Technologies to harness the power of ‘spiroligomers’ to rapidly build new small molecules for Longevity therapies.

Far from the world of stock market speculation, most investors and start-ups in the Longevity sector know the importance of having a long-term, multi-decade vision. None know it better than Temple University Professor Christian Schafmeister, whose 20 years of academic research is now taking its first steps towards commercialisation in the form of his new start-up – ThirdLaw Technologies.

Longevity.Technology: When we catch up on a Zoom call with Schafmeister, he is in an almost empty lab space – eagerly awaiting the arrival of mass spectrometers he has just purchased. This is clearly a company in its earliest stages. So what’s it all about? 

“We are starting up a company to develop an artificial immune system,” says Schafmeister. “We’re making very large libraries of artificial molecules that could bind to protein surfaces.”

At the core of ThirdLaw’s approach are ‘spiroligomers’ – a new type of chemical entity that combines the functional group richness of peptides and proteins with the properties of small molecules.

“Proteins are these long chains of amino acids that fold into a three dimensional shape and do something amazing – I wanted to build molecules like that,” says Schafmeister. “But the problem with proteins and every other approach to this is trying to figure out how this long flexible molecule will fold into a three dimensional shape.”

Making this challenge a key focus of his work at Temple University, Schafmeister came up with the idea for spiroligomers – using building blocks that are like amino acids but, instead of connecting through one bond, which allows rotational flexibility, his building blocks connect through two bonds.

“So you make building blocks that are rings, and you connect them through rings, and so you build ladder molecules,” he says. “And you could programme the shape of those ladder molecules by controlling their stereochemistry, the shapes of the rings, and how you put them together.”

“The clearest Longevity application for spiroligomers is developing catalysts that can cleave the glucosepane crosslinks to achieve advanced glycation endpoint (AGE) products.”

By achieving this, Schafmeister is able to create molecules that present as reactive groups like the side chains of amino acids, and hold them in a particular three dimensional constellation. This enables spiroligomers to do things like bind protein surfaces, or point them inwards to create pockets that enable catalysis and speed-up select chemical reactions.

“We’ve made molecules that bind to protein, we’ve made molecules that accelerate chemical reactions, we’re making molecules that can assemble to make little triangular pores that we can crosslink into membranes that could then filter things through these pores selectively,” says Schafmeister. “Just like what proteins can do – except that we can control it with the ability to control the shape of the molecules. And if you control the shape, you control what they do.”

From a Longevity perspective, ThirdLaw’s technology is potentially ground-breaking. Aging leads to progressive loss of elasticity and stiffening of tissues such as joints, cartilage, arteries, lungs and skin – caused by cross-linking in collagen due to a product called glucosepane.

A technology that could cleave glucosepane would potentially allow bound proteins to move freely again, and prevent age-related stiffening.

“The clearest [Longevity application for spiroligomers] is developing catalysts that can cleave the glucosepane crosslinks to achieve advanced glycation endpoint (AGE) products,” says Schafmeister. “That’s a clear goal and something that I think is unique to what we’re doing. We could do it in the next year – but it’s just a question of resources.”

ThirdLaw’s primary focus at this point is on developing artificial antibodies, a project for which its has received $7 million in funding from the US Department of Defense.

“They wanted technologies that could replace antibodies, because antibodies suck,” says Schafmeister. “They are fragile, they fall apart when you get them at the wrong temperature, they’re hard to make, it’s hard to control their quality. This is why we’ve got all these antibody tests on the market that are giving false negatives – the proteins are denaturing. Proteins are just really fragile, delicate things.”

Three years ago, Schafmeister told the DoD that he could solve this challenge and has been working towards this ever since.

“What it turned into is an artificial immune system that could rapidly develop lateral flow assays,” he says, describing tests that come in plastic cartridges, similar to a pregnancy test, where you put a drop of blood on an input port, add some liquid and red lines appear if there’s a positive response.

“It’s like we have the first transistor and now we’re starting to build integrated circuits with them. I’d like to be the Texas Instruments of molecular nanotechnology. These building blocks can do that, and there’s nothing else that can – everyone else is looking in the wrong place.”

“So that’s what I’ve been doing – and then we got hit by the pandemic – and then all of a sudden everybody understands what I’m trying to do,” says Schafmeister. “Let’s say in December when we knew that COVID was around, we get some of the live virus and then we take our large library of molecules, screen them against COVID-19, we identify ones that bind it and then we quickly snap together these tests that would give you a point-of-care test for the virus. All within six weeks.”

The $7 million funding should give ThirdLaw about two years to develop and demonstrate the technology, which Schafmeister describes as ”a really tight schedule.” His primary focus is now on scaling up the chemistry – to start making the ladder molecules on automate synthesisers, purify them, turn them into multimillion member libraries and start screening them against biological targets.

“We’re 20 years ahead of anyone making these things and they’re not easy to make,” says Schafmeister. “It’s like we have the first transistor and now we’re starting to build integrated circuits with them. I’d like to be the Texas Instruments of molecular nanotechnology. These building blocks can do that, and there’s nothing else that can – everyone else is looking in the wrong place.”

Professor Schafmeister is a speaker at October’s rescheduled Undoing Aging 2020 conference in Berlin.

Images courtesy of Professor Schafmeister