دورية أكاديمية
Facile discovery of surrogate cytokine agonists.
| العنوان: | Facile discovery of surrogate cytokine agonists. |
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| المؤلفون: | Yen, Michelle, Ren, Junming, Liu, Qingxiang, Glassman, Caleb R, Sheahan, Timothy P, Picton, Lora K, Moreira, Fernando R, Rustagi, Arjun, Jude, Kevin M, Zhao, Xiang, Blish, Catherine A, Baric, Ralph S, Su, Leon L, Garcia, K Christopher |
| المصدر: | Cell ; ISSN:1097-4172 ; Volume:185 ; Issue:8 |
| بيانات النشر: | Elsevier Science |
| سنة النشر: | 2022 |
| المجموعة: | PubMed Central (PMC) |
| مصطلحات موضوعية: | SARS-CoV-2, VHH, bispecific antibodies, cell signaling, cytokine engineering, interferon, interleukin-10, interleukin-2, scFv |
| الوصف: | Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.1016/j.cell.2022.02.025Test; https://pubmed.ncbi.nlm.nih.gov/35325595Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021867Test/ |
| DOI: | 10.1016/j.cell.2022.02.025 |
| الإتاحة: | https://doi.org/10.1016/j.cell.2022.02.025Test https://pubmed.ncbi.nlm.nih.gov/35325595Test https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021867Test/ |
| حقوق: | Copyright © 2022 Elsevier Inc. All rights reserved. |
| رقم الانضمام: | edsbas.F14F1991 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.cell.2022.02.025 |
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