Mimics of Enzymes and Antibodies for Glycans and Other Biological Targets

Mimics of Enzymes and Antibodies for Glycans and Other Biological Targets Project Summary/Abstract Molecular recognition and catalysis are the foundations for nearly all biological processes. Scientists have developed strong abilities to inhibit biomolecules at their ligand- binding or catalytic sites. However, when it comes to complex glycans, long strands of peptides, or proteins on nonligand-binding sites, it remains difficult to have supramolecular hosts/materials with biologically competitive binding affinity and specificity. Scientists have long argued that enzymes are “not different, just better” than synthetic catalysts. Inability to construct substrate-tailored active sites with precisely installed functional groups, however, has prevented researchers from accomplishing the catalytic feats of even relatively simple enzymes. The PI’s group has developed water-soluble, protein-sized, molecularly imprinted nanoparticles (MINPs) to bind carbohydrates with micromolar affinities and peptides with tens of nanomolar affinities. In the most recent R01 grant, MINPs have been converted into synthetic mimics of glycosidase and esterase with enzyme-like specificity and proficiency ((kcat/Km)/kuncat = 109–15 M-1) that operate under physiological conditions. In the next five years, the PI seeks to develop (a) efficient MINP-based artificial enzymes for selective hydrolysis of glycans, esters, and amides and (b) MINP–MINP conjugates for complex biomolecules such as glycoproteins and post-translationally modified proteins. The MINP glycosidase mimics are designed to cleave sialic acid-containing glycans and the glycosidic bonds in the core 2, 4, 6 of mucin-type O- glycans that currently lack suitable enzymes for cleavage. The MINP–MINP conjugates will be used to bind two separate epitopes on a biomolecular target, including glycoproteins and proteins with posttranslational modifications (PTMs). MINPs have already enabled applications/collaborations for controlling peptide/protein PTMs, elucidation of T cell signaling, and targeted degradation of amyloid proteins in neuron cells. All these applications depend critically on the strong and selective binding of MINPs for their biological targets in water, as well as their abilities to penetrate cell membranes. As their binding and catalytic properties are further enhanced, new applications are expect to emerge and new collaborations be made possible, to help solve important biomedical problems that could benefit from robust, designable, water-soluble synthetic mimics of antibodies and enzymes. Project Number: 5R35GM156461-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Yan Zhao | Institution: IOWA STATE UNIVERSITY, AMES, IA | Award Amount: $382,500 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1-MBBC-B(55)R] View on NIH RePORTER: https://reporter.nih.gov/project-details/11321532