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ACS Nano. 2020 Jan 28;14(1):185-195. doi: 10.1021/acsnano.9b07498. Epub 2019 Dec 2.

Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.

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The Molecular Foundry , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.
Department of Bioengineering and Therapeutic Sciences , University of California, San Francisco , San Francisco , California 94158 , United States.
Department of Chemistry , New York University , New York , New York 10003 , United States.
Physical Sciences Division , Pacific Northwest National Laboratory , Richland , Washington 99352 , United States.
Chan Zuckerberg Biohub , San Francisco , California 94158 , United States.


The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials.


bioinspired polymers; combinatorial display; multivalent molecular recognition; protein-mimetic materials; two-dimensional nanomaterials


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