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

Abstract

The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity make them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies has prompted exploration of a variety of new, 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, conformationallyconstrained 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 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.more » This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials.« less

Authors:
 [1]; ORCiD logo [2];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [4]; ORCiD logo [4];  [1]; ORCiD logo [1];  [1];  [1]; ORCiD logo [1]; ORCiD logo [4];  [5]; ORCiD logo [6]; ORCiD logo [1]
+ Show Author Affiliations
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Foundry
  2. Univ. of California, San Francisco, CA (United States). Dept of Bioengineering and Therapeutic Sciences
  3. New York Univ. (NYU), NY (United States). Dept. of Chemistry
  4. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Physical Sciences Div.
  5. Department of Chemistry, New York University, New York, New York 10003, United States
  6. Univ. of California, San Francisco, CA (United States). Dept of Bioengineering and Therapeutic Sciences; Chan Zuckerberg Biohub, San Francisco, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); DARPA Fold F(x) program.
OSTI Identifier:
1619149
Alternate Identifier(s):
OSTI ID: 1659114
Report Number(s):
PNNL-SA-155692
Journal ID: ISSN 1936-0851; ark:/13030/qt13n2z6v4
Grant/Contract Number:  
AC02-05CH11231; AC05-76RL01830
Resource Type:
Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 1936-0851
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; protein-mimetic materials; multivalent molecular recognition; combinatorial display; two-dimensional nanomaterials, bioinspired polymers; two-dimensional

Citation Formats

Kim, Jae Hong, Kim, Samuel C., Kline, Mark A., Grzincic, Elissa M., Tresca, Blakely W., Cardiel, Joshua, Karbaschi, Mohsen, Dehigaspitiya, Dilani C., Chen, Yulin, Udumula, Venkatareddy, Jian, Tengyue, Murray, Daniel J., Yun, Lisa, Connolly, Michael D., Liu, Jianfang, Ren, Gang, Chen, Chun-Long, Kirshenbaum, Kent, Abate, Adam R., and Zuckermann, Ronald N. Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets. United States: N. p., 2019. Web. doi:10.1021/acsnano.9b07498.
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Kim, Jae Hong, Kim, Samuel C., Kline, Mark A., Grzincic, Elissa M., Tresca, Blakely W., Cardiel, Joshua, Karbaschi, Mohsen, Dehigaspitiya, Dilani C., Chen, Yulin, Udumula, Venkatareddy, Jian, Tengyue, Murray, Daniel J., Yun, Lisa, Connolly, Michael D., Liu, Jianfang, Ren, Gang, Chen, Chun-Long, Kirshenbaum, Kent, Abate, Adam R., & Zuckermann, Ronald N. Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets. United States. https://doi.org/10.1021/acsnano.9b07498
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Kim, Jae Hong, Kim, Samuel C., Kline, Mark A., Grzincic, Elissa M., Tresca, Blakely W., Cardiel, Joshua, Karbaschi, Mohsen, Dehigaspitiya, Dilani C., Chen, Yulin, Udumula, Venkatareddy, Jian, Tengyue, Murray, Daniel J., Yun, Lisa, Connolly, Michael D., Liu, Jianfang, Ren, Gang, Chen, Chun-Long, Kirshenbaum, Kent, Abate, Adam R., and Zuckermann, Ronald N. Mon . "Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets". United States. https://doi.org/10.1021/acsnano.9b07498. https://www.osti.gov/servlets/purl/1619149.
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@article{osti_1619149,
title = {Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets},
author = {Kim, Jae Hong and Kim, Samuel C. and Kline, Mark A. and Grzincic, Elissa M. and Tresca, Blakely W. and Cardiel, Joshua and Karbaschi, Mohsen and Dehigaspitiya, Dilani C. and Chen, Yulin and Udumula, Venkatareddy and Jian, Tengyue and Murray, Daniel J. and Yun, Lisa and Connolly, Michael D. and Liu, Jianfang and Ren, Gang and Chen, Chun-Long and Kirshenbaum, Kent and Abate, Adam R. and Zuckermann, Ronald N.},
abstractNote = {The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity make them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies has prompted exploration of a variety of new, 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, conformationallyconstrained 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 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.},
doi = {10.1021/acsnano.9b07498},
journal = {ACS Nano},
number = 1,
volume = 14,
place = {United States},
year = {Mon Dec 02 00:00:00 EST 2019},
month = {Mon Dec 02 00:00:00 EST 2019}
}
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https://doi.org/10.1021/acsnano.9b07498
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