Key result
Catalytically inactive NS3 protease and antiviral peptides can be displaced by FDA-approved drugs to allosterically regulate Cre recombinase and modulate cellular processes.
Why the study?
Effective chemical inducer systems to control protein activity for scientific study, synthetic biology, and cell therapy must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties.
The development of an allosteric Cre regulation system using NS3 ligands enables orthogonal recombination tools in eukaryotic cells and divergent organisms.
NS3-peptide systems expand drug-inducible protein control; leaves open synthetic biology and cell therapy uses pending validation.
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 and non-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, and split-protein complementation. With our developed system, we invented 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 and FDA-approved antiviral drugs was evaluated on Modulation of transcription, cell signaling, and split-protein complementation. Catalytically inactive NS3 protease and antiviral peptides can be displaced by FDA-approved drugs to allosterically regulate Cre recombinase and modulate cellular processes.
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