ArticleThe Journal of biological chemistry2016
Design and Optimization of Anti-amyloid Domain Antibodies Specific for β-Amyloid and Islet Amyloid Polypeptide.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils.Protein science : a publication of the Protein Society · 2025Article
- Toward Drug-Like Multispecific Antibodies by Design.International journal of molecular sciences · 2020Review
- Functional Mammalian Amyloids and Amyloid-Like Proteins.Life (Basel, Switzerland) · 2020Review
- Using protein engineering to understand and modulate aggregation.Current opinion in structural biology · 2020Review
- Role of surface oxygen-containing functional groups of graphene oxide quantum dots on amyloid fibrillation of two model proteins.PloS one · 2020Article
- Nature-inspired design and evolution of anti-amyloid antibodies.The Journal of biological chemistry · 2019Article
- Single-Domain Antibodies as Therapeutic and Imaging Agents for the Treatment of CNS Diseases.Antibodies (Basel, Switzerland) · 2019Review
- Net charge of antibody complementarity-determining regions is a key predictor of specificity.Protein engineering, design & selection : PEDS · 2018Article
- Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility.Biochemical engineering journal · 2018Article
- Multi-Pronged Interactions Underlie Inhibition of α-Synuclein Aggregation by β-Synuclein.Journal of molecular biology · 2018Article
- Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies.Nature reviews. Neurology · 2018Review
- Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.eLife · 2017Article
- Arginine mutations in antibody complementarity-determining regions display context-dependent affinity/specificity trade-offs.The Journal of biological chemistry · 2017Article
- Methods of probing the interactions between small molecules and disordered proteins.Cellular and molecular life sciences : CMLS · 2017Review
- Small molecule probes of protein aggregation.Current opinion in chemical biology · 2017Review
- Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability.Scientific reports · 2017Article
- Engineered Autonomous Human Variable Domains.Current pharmaceutical design · 2016Review
- Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity.The Journal of biological chemistryArticle
- Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Antibodies with conformational specificity are important for detecting and interfering with polypeptide aggregation linked to several human disorders. We are developing a motif-grafting approach for designing lead antibody candidates specific for amyloid-forming polypeptides such as the Alzheimer peptide (Aβ). This approach involves grafting amyloidogenic peptide segments into the complementarity-determining regions (CDRs) of single-domain (VH) antibodies. Here we have investigated the impact of polar mutations inserted at the edges of a large hydrophobic Aβ42 peptide segment (Aβ residues 17-42) in CDR3 on the solubility and conformational specificity of the corresponding VH domains. We find that VH expression and solubility are strongly enhanced by introducing multiple negatively charged or asparagine residues at the edges of CDR3, whereas other polar mutations are less effective (glutamine and serine) or ineffective (threonine, lysine, and arginine). Moreover, Aβ VH domains with negatively charged CDR3 mutations show significant preference for recognizing Aβ fibrils relative to Aβ monomers, whereas the same VH domains with other polar CDR3 mutations recognize both Aβ conformers. We observe similar behavior for a VH domain grafted with a large hydrophobic peptide from islet amyloid polypeptide (residues 8-37) that contains negatively charged mutations at the edges of CDR3. These findings highlight the sensitivity of antibody binding and solubility to residues at the edges of CDRs, and provide guidelines for designing other grafted antibody fragments with hydrophobic binding loops.
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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.