Key result
Catalytically inactive NS3 protease bound to antiviral peptides can be displaced by FDA-approved drugs to modulate protein activity and allosterically regulate Cre recombinase in eukaryotic cells.
Why the study?
Effective chemical inducer systems for controlling protein activity must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties for broad use.
The study develops a novel chemical inducer system using inactive NS3 protease and antiviral drugs to allosterically regulate protein activity, including Cre recombinase, in eukaryotic and prokaryotic cells.
NS3-based systems enable tunable protein control with low crosstalk; leaves open therapeutic validation in cell therapy applications.
Chemical control of protein activity is a powerful tool for scientific study, synthetic biology, and cell therapy; however, for broad use, effective chemical inducer systems must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties. Accordingly, the drug-controllable proteolytic activity of hepatitis C cis- protease NS3 and its associated antiviral drugs have been used to regulate protein activity and gene modulation. These tools advantageously exploit non-eukaryotic/prokaryotic proteins and clinically approved inhibitors. Here we expand the toolkit by utilizing catalytically inactive NS3 protease as a high affinity binder to genetically encoded, antiviral peptides. Through our approach, we create NS3-peptide complexes that can be displaced by FDA-approved drugs to modulate transcription, cell signaling, split-protein complementation. With our developed system, we discover a new mechanism to allosterically regulate Cre recombinase. Allosteric Cre regulation with NS3 ligands enables orthogonal recombination tools in eukaryotic cells and functions in divergent organisms to control prokaryotic recombinase activity.
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Tague et al. (2023) studied this question. NS3-peptide complexes displaced by FDA-approved drugs was evaluated on Modulation of transcription, cell signaling, split-protein complementation, and allosteric regulation of Cre recombinase. Catalytically inactive NS3 protease bound to antiviral peptides can be displaced by FDA-approved drugs to modulate protein activity and allosterically regulate Cre recombinase in eukaryotic cells.
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