TY - JOUR
T1 - Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets
AU - Kim, Jae Hong
AU - Kim, Samuel C.
AU - Kline, Mark A.
AU - Grzincic, Elissa M.
AU - Tresca, Blakely W.
AU - Cardiel, Joshua
AU - Karbaschi, Mohsen
AU - Dehigaspitiya, Dilani C.
AU - Chen, Yulin
AU - Udumula, Venkatareddy
AU - Jian, Tengyue
AU - Murray, Daniel J.
AU - Yun, Lisa
AU - Connolly, Michael D.
AU - Liu, Jianfang
AU - Ren, Gang
AU - Chen, Chun Long
AU - Kirshenbaum, Kent
AU - Abate, Adam R.
AU - Zuckermann, Ronald N.
N1 - Funding Information:
This project was funded by the DARPA Fold F(x) program. Portions of this work were conducted at the Molecular Foundry at Lawrence Berkeley National Laboratory, which is supported by the Office of Science, Office of Basic Energy Sciences, U.S. Department of Energy under Contract No. DEAC02-05CH11231. Pacific Northwest National Laboratory (PNNL) is a multiprogram national laboratory operated for Department of Energy by Battelle under Contracts No. DE-AC05-76RL01830. The authors thank R. Garcia for help with peptoid synthesis.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/1/28
Y1 - 2020/1/28
N2 - 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.
AB - 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.
KW - bioinspired polymers
KW - combinatorial display
KW - multivalent molecular recognition
KW - protein-mimetic materials
KW - two-dimensional nanomaterials
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U2 - 10.1021/acsnano.9b07498
DO - 10.1021/acsnano.9b07498
M3 - Article
C2 - 31789500
AN - SCOPUS:85076743828
SN - 1936-0851
VL - 14
SP - 185
EP - 195
JO - ACS nano
JF - ACS nano
IS - 1
ER -