ArticleProceedings of the National Academy of Sciences of the United States of America2010
CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 137 papers.
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137 citing papers in PubMed, 244 citations in OpenAlex.
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- Nanobodies unlock new mechanisms to target G protein-coupled receptors.Molecular pharmacology · 2026Review
- Nanobody-Based Bioconjugates as Potent and Broadly Active Inhibitors of HIV Entry.Journal of the American Chemical Society · 2026Article
- Searching for a HIV-1 Cure.Theranostics · 2026Review
- TR-FRET between engineered nanobodies reveals the existence of endogenous CXCR4 oligomers.Communications biology · 2025Article
- Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies.Nature communications · 2025Article
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- Progress toward new function and design of extracellular G protein-coupled receptor nanobodies.Molecular pharmacology · 2025Review
- Development and characterization of a novel NEIL1 nanobody.DNA repair · 2025Article
- Small but Mighty: Nanobodies in the Fight Against Infectious Diseases.Biomolecules · 2025Review
- Selective PET imaging of CXCR4 using the AlEuropean journal of nuclear medicine and molecular imaging · 2025Article
- Epitope-directed selection of GPCR nanobody ligands with evolvable function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Deep Thought on the HIV Cured Cases: Where Have We Been and What Lies Ahead?Biomolecules · 2025Review
- The Use of Biologics for Targeting GPCRs in Metastatic Cancers.Biotech (Basel (Switzerland)) · 2025Review
- Cell-free protein synthesis platforms for accelerating drug discovery.Biotechnology notes (Amsterdam, Netherlands) · 2025Review
77 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The important family of G protein-coupled receptors has so far not been targeted very successfully with conventional monoclonal antibodies. Here we report the isolation and characterization of functional VHH-based immunoglobulin single variable domains (or nanobodies) against the chemokine receptor CXCR4. Two highly selective monovalent nanobodies, 238D2 and 238D4, were obtained using a time-efficient whole cell immunization, phage display, and counterselection method. The highly selective VHH-based immunoglobulin single variable domains competitively inhibited the CXCR4-mediated signaling and antagonized the chemoattractant effect of the CXCR4 ligand CXCL12. Epitope mapping showed that the two nanobodies bind to distinct but partially overlapping sites in the extracellular loops. Short peptide linkage of 238D2 with 238D4 resulted in significantly increased affinity for CXCR4 and picomolar activity in antichemotactic assays. Interestingly, the monovalent nanobodies behaved as neutral antagonists, whereas the biparatopic nanobodies acted as inverse agonists at the constitutively active CXCR4-N3.35A. The CXCR4 nanobodies displayed strong antiretroviral activity against T cell-tropic and dual-tropic HIV-1 strains. Moreover, the biparatopic nanobody effectively mobilized CD34-positive stem cells in cynomolgus monkeys. Thus, the nanobody platform may be highly effective at generating extremely potent and selective G protein-coupled receptor modulators.
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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.