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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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-01, Vol.119 (4), p.1
Main Authors: Vanderschuren, Koen, Arranz-Gibert, Pol, Khang, Minsoo, Hadar, Dagan, Gaudin, Alice, Yang, Fan, Folta-Stogniew, Ewa, Saltzman, W Mark, Amiram, Miriam, Isaacs, Farren J
Format: Article
Language:English
Subjects:
Ablation
Albumin
Albumins
Amino Acids
Animals
Biological Sciences
Biopolymers
Biopolymers - chemistry
Biotechnology
Conjugation
Elastin
Genetic code
Half-Life
Immunogenicity
Lipids
Lipids - chemistry
Materials science
Mice
Peptides
Peptides - chemistry
Physical Sciences
Polypeptides
Protein Engineering - methods
Proteins
Proteins - chemistry
Side effects
Synthetic Biology - methods
Toxicity
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Summary: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 -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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2103099119