Christian Schafmeister Saturday, May 28, 2022

Title: Towards Developing Molecular Lego Catalysts For Cleaving Intramolecular Cross-links

Abstract: Spiroligomers are the most advanced and one of only three examples of "molecular Lego" (a term coined by Nobel Laureate Prof. Fraser Stoddart in the 70's) - large, shape controlled, molecules formed by joining cyclic building blocks through pairs of covalent bonds. Spiroligomers are highly functionalized, shape-programmable ladder-oligomers formed by joining functionalized, stereochemically pure bis-amino acids through pairs of amide bonds. Spiroligomers are a means to construct robust nanoscale structures with exquisite control over their three-dimensional structures. We have been working for two decades towards the challenging goal to develop small catalysts that can hydrolyze glucosepane cross-links in the extracellular matrix - cross-links that are likely involved in many diseases of aging. We have previously shown that spiroligomers can modulate protein function by binding grooves on protein surfaces and disrupting protein-protein interactions.  We have also demonstrated four examples of small spiroligomers that act as catalysts, accelerating chemical reactions. Over the last three years we have scaled up the synthesis of bis-amino acids to a 30-kilogram scale. We have demonstrated the efficient incorporation of the fluorenylmethyloxycarbonyl (Fmoc) protecting group at hundreds of gram scale and the incorporation of more than 25 diverse functional groups on four stereochemically pure monomers. In the past year, we have prepared more than 600 spiroligomers with molecular weights in the range of 1,300 to 1,500 Daltons using automated peptide synthesizers at a 10-100 milligram scale. We have assembled these spiroligomers into 2.5 million macromolecules approximately 5,000 Da and identified some that bind proteins. We will describe some of this work and a plan for how we will develop these molecules as robust "catalytic therapeutics", enzyme-like molecules that are small enough to penetrate the extracellular matrix (5,000 Da), remain invisible to the immune system, and catalytically and selectively cleave glucosepane cross-links involved in aging.