This popular science article takes a brief look at work on spiroligomers, a solution for some of the hard problems in the design of custom molecules. This might be applied to building molecules that can break glucosepane, the molecule involved in the overwhelming majority of persistent, harmful cross-links in aged human tissues. These cross-links build up with age, linking together structural molecules of the extracellular matrix. This produces a loss of elasticity and increasing stiffness in tissues such as skin and blood vessel walls, the second of which is an important contributing cause of hypertension and consequent cardiovascular disease. Now that glucosepane can be cost-effectively synthesized, an advance funded by the SENS Research Foundation, we should expect to see more novel approaches to drug design being applied to cross-linking.
Christian Schafmeister’s academic research is now taking its first steps towards commercialisation in the form of his new start-up – ThirdLaw Technologies. The company seeks to harness the power of ‘spiroligomers’ to rapidly build new small molecules. “We are starting up a company to develop an artificial immune system. We’re making very large libraries of artificial molecules that could bind to protein surfaces. 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. 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.”
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,. 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.”
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. “The clearest aging-related application for spiroligomers is developing catalysts that can cleave the glucosepane crosslinks. 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.”