A kinetic proofreading model for bispecific protein degraders

Bispecific protein degraders (BPDs) engage the ubiquitin–proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmacokinetics and pharmacodynamics 2021-02, Vol.48 (1), p.149-163
Main Authors: Bartlett, Derek W., Gilbert, Adam M.
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Degradation
Editing
Lymphocytes T
Original Paper
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Proofreading
Proteasomes
Proteins
Signal transduction
T cell receptors
Ubiquitin
Ubiquitin-protein ligase
Veterinary Medicine/Veterinary Science
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Bispecific protein degraders (BPDs) engage the ubiquitin–proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs that includes the reaction network governing ternary complex formation and degradation via the UPS. A critical element of the model framework is a multi-step process that results in a time delay between ternary complex formation and protein degradation, thereby balancing ternary complex stability against UPS degradation rates akin to the kinetic proofreading concept that has been proposed to explain the accuracy and specificity of biological processes including protein translation and T cell receptor signal transduction. Kinetic proofreading likely plays a central role in the cell’s ability to regulate substrate recognition and degradation by the UPS, and the model presented here applies this concept in the context of a quantitative pharmacokinetic (PK)-pharmacodynamic (PD) framework to inform the design of potent and selective BPDs.
ISSN:1567-567X
1573-8744
DOI:10.1007/s10928-020-09722-z