ArticleNature communications2014
A system for the continuous directed evolution of proteases rapidly reveals drug-resistance mutations.
Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 106 citations in OpenAlex.
- Article
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- Adaptive cargo deletion as an evolutionary dead-end during phage-based directed evolution.BMC research notes · 2026Article
- Ratiometric transcriptional activation by protein degradation.bioRxiv : the preprint server for biology · 2026Article
- Phage-assisted evolution of allosteric protein switches.Nature communications · 2026Article
- Combing Directed Enzyme Evolution with Metabolic Engineering to Develop Efficient Microbial Cell Factories.Chem & bio engineering · 2025Review
- PERRC: Protease Engineering with Reactant Residence Time Control.ACS synthetic biology · 2025Article
- A generalizable approach for programming protease-responsive conformationally inhibited artificial transcriptional factors.Nature communications · 2025Article
- Programmable gene insertion in human cells with a laboratory-evolved CRISPR-associated transposase.Science (New York, N.Y.) · 2025Article
- EvoAI enables extreme compression and reconstruction of the protein sequence space.Nature methods · 2025Article
- Continuous evolution of compact protein degradation tags regulated by selective molecular glues.Science (New York, N.Y.) · 2024Article
- EvoAI enables extreme compression and reconstruction of the protein sequence space.Research square · 2024Article
- Gene birth in a model of non-genic adaptation.BMC biology · 2023Article
- Virus-assisted directed evolution of biomolecules.Current opinion in chemical biology · 2023Review
- Controlled Protein Activities with Viral Proteases, Antiviral Peptides, and Antiviral Drugs.ACS chemical biology · 2023Article
- Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity.Nature biotechnology · 2023Article
- Engineering Nitrogenases for Synthetic Nitrogen Fixation: From Pathway Engineering to Directed Evolution.Biodesign research · 2023Review
- Exploiting spatial dimensions to enable parallelized continuous directed evolution.Molecular systems biology · 2022Article
- Making the cut with protease engineering.Cell chemical biology · 2022Review
- Disulfide-compatible phage-assisted continuous evolution in the periplasmic space.Nature communications · 2021Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The laboratory evolution of protease enzymes has the potential to generate proteases with therapeutically relevant specificities and to assess the vulnerability of protease inhibitor drug candidates to the evolution of drug resistance. Here we describe a system for the continuous directed evolution of proteases using phage-assisted continuous evolution (PACE) that links the proteolysis of a target peptide to phage propagation through a protease-activated RNA polymerase (PA-RNAP). We use protease PACE in the presence of danoprevir or asunaprevir, two hepatitis C virus (HCV) protease inhibitor drug candidates in clinical trials, to continuously evolve HCV protease variants that exhibit up to 30-fold drug resistance in only 1 to 3 days of PACE. The predominant mutations evolved during PACE are mutations observed to arise in human patients treated with danoprevir or asunaprevir, demonstrating that protease PACE can rapidly identify the vulnerabilities of drug candidates to the evolution of clinically relevant drug resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.