ArticlePLoS computational biology2012
Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 119 citations in OpenAlex.
- Mechanistic Insights into CFTR Potentiation by the Antimicrobial Peptide Esc(1-21): Direct Interaction with the NBD1-NBD2 Interface.ACS omega · 2026Article
- Sequence Engineering at Non-motif Modulator Residues Yields a Peptide That Effectively Targets a Single PDZ Protein in a Disease-relevant Cellular Context.Journal of molecular biology · 2026Article
- Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.Cellular & molecular biology letters · 2025Review
- Sequence engineering at non-motif modulator residues yields a peptide that effectively targets a single PDZ protein in a disease-relevant cellular context.bioRxiv : the preprint server for biology · 2025Article
- A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.PLoS pathogens · 2024Article
- DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.Protein engineering, design & selection : PEDS · 2024Article
- Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir.Npj viruses · 2024Article
- A comprehensive study of SARS-CoV-2 main protease (MbioRxiv : the preprint server for biology · 2023Article
- Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets.Protein science : a publication of the Protein Society · 2023Article
- Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets.bioRxiv : the preprint server for biology · 2023Article
- RESISTOR: A New OSPREY Module to Predict Resistance Mutations.Journal of computational biology : a journal of computational molecular cell biology · 2022Article
- Tryptophan mutations in G3BP1 tune the stability of a cellular signaling hub by weakening transient interactions with Caprin1 and USP10.The Journal of biological chemistry · 2022Article
- Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives.Journal of medicinal chemistry · 2022Review
- Computational Tools and Strategies to Develop Peptide-Based Inhibitors of Protein-Protein Interactions.Methods in molecular biology (Clifton, N.J.) · 2022Review
- Inhibition of Viral Membrane Fusion by Peptides and Approaches to Peptide Design.Pathogens (Basel, Switzerland) · 2021Review
- Automated affinity selection for rapid discovery of peptide binders.Chemical science · 2021Article
- Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface.PLoS computational biology · 2020Article
- Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering.International journal of molecular sciences · 2020Review
- Minimization-Aware RecursiveJournal of computational biology : a journal of computational molecular cell biology · 2020Article
- A general-purpose protein design framework based on mining sequence-structure relationships in known protein structures.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors"), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers") that rescue ΔF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.
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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.