Chemically Modified DNA Aptamers Bind Interleukin-6 with High Affinity and Inhibit Signaling by Blocking Its Interaction with Interleukin-6 Receptor
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Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune and inflammatory responses, and its overproduction is a hallmark of inflammatory diseases. Inhibition of IL-6 signaling with the anti-IL-6 receptor antibody tocilizumab has provided some clinical benefit to patients; however, direct cytokine inhibition may be a more effective option. We used the systematic evolution of ligands by exponential enrichment (SELEX) process to discover slow off-rate modified aptamers (SOMAmers) with hydrophobic base modifications that inhibit IL-6 signaling in vitro. Two classes of IL-6 SOMAmers were isolated from modified DNA libraries containing 40 random positions and either 5-(N-benzylcarboxamide)-2'-deoxyuridine (Bn-dU) or 5-[N-(1-naphthylmethyl)carboxamide]-2'-deoxyuridine (Nap-dU) replacing dT. These modifications facilitate the high affinity binding interaction with IL-6 and provide resistance against degradation by serum endonucleases. Post-SELEX optimization of one Bn-dU and one Nap-dU SOMAmer led to improvements in IL-6 binding (10-fold) and inhibition activity (greater than 20-fold), resulting in lead SOMAmers with sub-nanomolar affinity (Kd = 0.2 nm) and potency (IC50 = 0.2 nm). Although similar in inhibition properties, the two SOMAmers have unique sequences and different ortholog specificities. Furthermore, these SOMAmers were stable in human serum in vitro for more than 48 h. Both SOMAmers prevented IL-6 signaling by blocking the interaction of IL-6 with its receptor and inhibited the proliferation of tumor cells in vitro as effectively as tocilizumab. This new class of IL-6 inhibitor may be an effective therapeutic alternative for patients suffering from inflammatory diseases.
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This scalable and reproducible top-down nanoproteomics approach can be generally applied to other low-abundance plasma/serum proteins of interest, such as cytokines or growth factors, if the NPs can be functionalized with a suitable affinity reagent.
“Beyond cTnI, we expect that this scalable and reproducible top-down nanoproteomics approach can be generally applied to other low-abundance plasma/serum proteins of interest, such as cytokines or growth factors, if the NPs can be functionalized with a suitable affinity reagent55,56.”
From Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum (2020) · cites this paper as [56]
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Cell-specific aptamers as potential drugs in therapeutic applications: A review of current progress
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Oligonucleotide Aptamer-Mediated Precision Therapy of Hematological Malignancies
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The Potential of Aptamer-Mediated Liquid Biopsy for Early Detection of Cancer
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Aptamers: A Feasible Technology in Cancer Immunotherapy
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Novel insights into the role of aptamers in the fight against cancer
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Pharmacokinetic Properties of DNA Aptamers with Base Modifications
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Self-citationA highly sensitive and selective impedimetric aptasensor for interleukin-17 receptor A
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Molecular modeling and SPRi investigations of interleukin 6 (IL6) protein and DNA aptamers
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Virus-based SELEX (viro-SELEX) allows development of aptamers targeting knotty proteins
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Nucleic Acid Aptamer: A Novel Potential Diagnostic and Therapeutic Tool for Leukemia
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Chemically Modified Aptamers in Biological Analysis
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Measuring Antibody-Antigen Binding Kinetics Using Surface Plasmon Resonance
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Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA
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Targeting IL-6 by engineered Lactococcus lactis via surface-displayed affibody
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Side chain determinants of biopolymer function during selection and replication
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Broadly neutralizing aptamers to SARS-CoV-2: A diverse panel of modified DNA antiviral agents
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Aptamers as the chaperones (Aptachaperones) of drugs-from siRNAs to DNA nanorobots
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Therapeutic Interventions into Innate Immune Diseases by Means of Aptamers
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Recent Advances in Aptamers Targeting Immune System
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The emerging potential of Aptamers as therapeutic agents in infection and inflammation
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Aptamer-based therapy for targeting key mediators of cancer metastasis (Review)
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Selection of optimised ligands by fluorescence-activated bead sorting
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Aptamers Against Immunologic Targets: Diagnostic and Therapeutic Prospects
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Nucleobase modification by an RNA enzyme
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- Authors
- Gupta, S., Hirota, M., Waugh, S. M., Murakami, I., Suzuki, T., Muraguchi, M., Shibamori, M., Ishikawa, Y., Jarvis, T. C., Carter, J. D., Zhang, C., Gawande, B., Vrkljan, M., Janjic, N., & Schneider, D. J.
- Affiliations
- SomaLogic (United States) (US)
- Corresponding author
- Schneider, Daniel J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 289
- Issue
- 12
- Pages
- 8706-8719
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3961692
- OpenAlex
- W2084203294
- Cited by
- 151
- References
- 52
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 7 · 2023: 10 · 2022: 16 · 2021: 9 · 2020: 13 · 2019: 17 · 2018: 14 · 2017: 13 · 2016: 14 · 2015: 16 · 2014: 6
- FWCI
- 6.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- interleukin-6, SOMAmer, IL-6 receptor, cytokine signaling inhibition, SELEX, serum stability, tumor cell proliferation, inflammatory diseases
- MeSH terms
- Interleukin-6 Inhibitors, Amino Acid Sequence, Animals, Anti-Inflammatory Agents, Base Sequence, Cricetulus, Humans, Macaca fascicularis, Molecular Sequence Data, Interleukin-6, CHO Cells, Receptors, Interleukin-6, Serum, Mice, Rats, SELEX Aptamer Technique, Aptamers, Nucleotide, Drug Discovery
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