ArticleProceedings of the National Academy of Sciences of the United States of America2023
Evolution of nanobodies specific for BCL11A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- The NanoBridge system for targeted post-translational modification of challenging proteins.bioRxiv : the preprint server for biology · 2026Article
- Targeted protein degradation for fetal hemoglobin induction: a new paradigm in β-hemoglobinopathy therapy.Biomarker research · 2026Review
- Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression.Nature communications · 2025Article
- BCL11A deficiency protects epidermis from UVB-induced damage through promotion of autophagy.Communications biology · 2025Article
- Solution structure of the Z0 domain from transcription repressor BCL11A sheds light on the sequence properties of protein-binding zinc fingers.Protein science : a publication of the Protein Society · 2025Article
- Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics.Chemical reviews · 2025Review
- Nanobody engineering: computational modelling and design for biomedical and therapeutic applications.FEBS open bio · 2025Review
- Hemoglobin Variants as Targets for Stabilizing Drugs.Molecules (Basel, Switzerland) · 2025Review
- Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains.The Journal of biological chemistry · 2025Article
- Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6.Structure (London, England : 1993) · 2024Article
- Linking Protein Stability to Pathogenicity: Predicting Clinical Significance of Single-Missense Mutations in Ocular Proteins Using Machine Learning.International journal of molecular sciences · 2024Article
- Chromatin remodellers as therapeutic targets.Nature reviews. Drug discovery · 2024Review
- In vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model.Nature communications · 2024Article
- Article
- Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Transcriptional Repressor BCL11A in Erythroid Cells.Advances in experimental medicine and biology · 2024Review
- Opportunities and challenges of protein-based targeted protein degradation.Chemical science · 2023Review
- Beyond canonical PROTAC: biological targeted protein degradation (bioTPD).Biomaterials research · 2023Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Transcription factors (TFs) control numerous genes that are directly relevant to many human disorders. However, developing specific reagents targeting TFs within intact cells is challenging due to the presence of highly disordered regions within these proteins. Intracellular antibodies offer opportunities to probe protein function and validate therapeutic targets. Here, we describe the optimization of nanobodies specific for BCL11A, a validated target for the treatment of hemoglobin disorders. We obtained first-generation nanobodies directed to a region of BCL11A comprising zinc fingers 4 to 6 (ZF456) from a synthetic yeast surface display library, and employed error-prone mutagenesis, structural determination, and molecular modeling to enhance binding affinity. Engineered nanobodies recognized ZF6 and mediated targeted protein degradation (TPD) of BCL11A protein in erythroid cells, leading to the anticipated reactivation of fetal hemoglobin (HbF) expression. Evolved nanobodies distinguished BCL11A from its close paralog BCL11B, which shares an identical DNA-binding specificity. Given the ease of manipulation of nanobodies and their exquisite specificity, nanobody-mediated TPD of TFs should be suitable for dissecting regulatory relationships of TFs and gene targets and validating therapeutic potential of proteins of interest.
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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.