Robust Sequence-defined Nanocages with Protein-mimetic Cavities - PROJECT SUMMARY/ABSTRACT Mimicking protein-like cavities and functions requires to precisely organize surface groups on well-defined, porous scaffolds to function in a concerted and orchestrated manner. Here, we propose to generate fully sequence-defined robust nanocages for selective, multivalent recognition and catalysis reminiscent of protein cavities. Building on the PI’s unique interdisciplinary expertise in supramolecular, organic, and computational chemistry, the primary objective is to create strategies to design and synthesize fully sequence-defined nanocages as artificial receptors for sensing biomolecules (e.g., enkephalins in the brain) and as selective artificial enzymes (e.g., for site-selective modification of peptides). We will direct the positioning of the endohedral functional groups (e.g., mono-, di-, or tripeptides) with chiral, sequence-defined covalent templates (e.g., sequence-defined peptide dendrimers and a-helical peptides), which will transfer their outer amino acids onto the endohedral sites of the nanocages in a stereocontrolled manner. The Schneebeli lab has synthesized and characterized robust, hydrazone-linked nanocages required to bulid the sequence-defined nanocages. These nanocages have been successfully applied as receptors for small molecules, and as size-selective polymerization catalysts, which lays the foundation for the proposed selective neuropeptide recognition and site- selective catalysis. We will pursue two parallel avenues to create the fully sequence defined nanocages. In Project 1, we will template nanocage formation directly in a sequence-defined manner, assembling the nanocages with hydrazone bonds (which are reversible under acidic conditions) and then cut out the templates. In Project 2, we will stereoselectively functionalize preformed [8+12]-nanocages (created with a novel, cyclotrimerization-based synthesis) with the help of a-helical peptide templates and equilibrating imine bonds, and then reduce the imine bonds and cut out the templates. This research is novel in the concept, synthetic approach, characterization, and applications, because (i) fully sequence-defined asymmetric nanocages represent a considerable shift in the current research of artificial molecular receptors and artificial enzymes, (ii) hydrazone-linked nanocages and cyclotrimerization-based nanocages syntheses (pioneered in the Schneebeli group) are powerful approaches to access large and chemically-robust nanocage frameworks capable of holding up to 12 endohedral functional groups with full sequence definition, and (iii) the creation of robust, protein-mimetic cavities may ultimately yield numerous advances in both fundamental structural and mechanistic knowledge of artificial receptor/artificial enzyme design. The proposed research is significant, because it will enable synthetic chemists to independently control the endohedral sites of porous nanocages, ultimately offering new opportunities and approaches to rapidly sense biomolecules and catalyze new, stereoselective chemical reactions for therapeutics development.
