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Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids
Koen Vanderschuren1,2, Pol Arranz-Gibert1,2, Minsoo Khang3
1Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06520.
Summary
Scientists engineered protein-drug fusions using genetically encoded sites for precise lipidation. This method extends therapeutic half-lives and enhances stability, offering broad applications in medicine and biotechnology.
Area of Science:
- Biotechnology
- Biochemistry
- Drug Development
Background:
- Biologics offer targeted treatment with fewer side effects but face limitations like short half-lives and immunogenicity.
- Peptide and protein therapeutics require strategies to improve stability and prolong efficacy in vivo.
- Genetically encoded methods offer precise control over biopolymer modification.
Purpose of the Study:
- To develop a method for extending the half-life of protein therapeutics.
- To create sequence-defined synthetic biopolymers with tunable properties.
- To establish a foundation for functionalized biopolymers with broad applications.
Main Methods:
- Utilized a genomically recoded organism to produce elastin-like polypeptide-protein fusions with multiple p-azidophenylalanine (pAzF) residues.
- Performed precise lipidation of pAzF residues for creating sequence-defined synthetic biopolymers.
- Assessed binding affinity to albumin and blood serum half-lives in a mouse model.
Main Results:
- Generated synthetic biopolymers with programmable albumin binding affinity.
- Achieved tunable blood serum half-lives ranging from 5% to 94% of albumin's half-life.
- Demonstrated that lipidation did not ablate the activity of model fusion proteins.
Conclusions:
- Genetically encoded bioorthogonal conjugation sites enable precise, multi-site lipidation to tune protein stability.
- This programmable approach can extend and tune the half-life of protein or peptide therapeutics.
- Established a technical foundation for producing functionalized biopolymers with programmable properties for medicine, materials science, and biotechnology.
