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Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids

The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these...

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Autores principales: Vanderschuren, Koen, Arranz-Gibert, Pol, Khang, Minsoo, Hadar, Dagan, Gaudin, Alice, Yang, Fan, Folta-Stogniew, Ewa, Saltzman, W. Mark, Amiram, Miriam, Isaacs, Farren J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794819/
https://www.ncbi.nlm.nih.gov/pubmed/35046019
http://dx.doi.org/10.1073/pnas.2103099119
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author Vanderschuren, Koen
Arranz-Gibert, Pol
Khang, Minsoo
Hadar, Dagan
Gaudin, Alice
Yang, Fan
Folta-Stogniew, Ewa
Saltzman, W. Mark
Amiram, Miriam
Isaacs, Farren J.
author_facet Vanderschuren, Koen
Arranz-Gibert, Pol
Khang, Minsoo
Hadar, Dagan
Gaudin, Alice
Yang, Fan
Folta-Stogniew, Ewa
Saltzman, W. Mark
Amiram, Miriam
Isaacs, Farren J.
author_sort Vanderschuren, Koen
collection PubMed
description The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide–protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin’s half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.
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spelling pubmed-87948192022-02-03 Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids Vanderschuren, Koen Arranz-Gibert, Pol Khang, Minsoo Hadar, Dagan Gaudin, Alice Yang, Fan Folta-Stogniew, Ewa Saltzman, W. Mark Amiram, Miriam Isaacs, Farren J. Proc Natl Acad Sci U S A Biological Sciences The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide–protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin’s half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology. National Academy of Sciences 2022-01-18 2022-01-25 /pmc/articles/PMC8794819/ /pubmed/35046019 http://dx.doi.org/10.1073/pnas.2103099119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Vanderschuren, Koen
Arranz-Gibert, Pol
Khang, Minsoo
Hadar, Dagan
Gaudin, Alice
Yang, Fan
Folta-Stogniew, Ewa
Saltzman, W. Mark
Amiram, Miriam
Isaacs, Farren J.
Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title_full Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title_fullStr Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title_full_unstemmed Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title_short Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
title_sort tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794819/
https://www.ncbi.nlm.nih.gov/pubmed/35046019
http://dx.doi.org/10.1073/pnas.2103099119
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