American journal of epidemiology
Authors: Zeki Al Hazzouri A, Jawadekar N, Kezios K, Caunca MR, Elfassy T, Calonico S, Kershaw KN, Yaffe K, Launer L, Elbejjani M, Grasset L, Manly J, Odden MC, Glymour MM
Authors: Davis JL, Ayakaka I, Ggita JM, Ochom E, Babirye D, Turimumahoro P, Gupta AJ, Mugabe FR, Armstrong-Hough M, Cattamanchi A, Katamba A
Authors: Smith RE, Sprague B, Henderson LM, Kerlikowske K, Miglioretti DL, Buist DSM, Wernli KJ, Onega T, Schifferdecker K, Jackson-Nefertiti G, Johnson D, Budesky J, Tosteson ANA
Authors: Mutchler MG, Wagner GJ, McDavitt B, Woldetsadik MA, Kegeles SM, El-Khoury C, Nogg KA, Klinger IA, Mokhbat J, Ballan EG
Authors: Vazquez SE, Mann SA, Bodansky A, Kung AF, Quandt Z, Ferré EMN, Landegren N, Eriksson D, Bastard P, Zhang SY, Liu J, Mitchell A, Mandel-Brehm C, Miao B, Sowa G, Zorn K, Chan AY, Shimizu C, Tremoulet A, Lynch K, Wilson MR, Kampe O, Dobbs K, Delmonte OM, Notarangelo LD, Burns JC, Casanova JL, Lionakis MS, Torgerson TR, Anderson MS, DeRisi JL
Authors: Masharani U, Strycker LA, Fisher L
Authors: Dube K, Eskaf S, Barr L, Palm D, Hogg E, Simoni J, Sugarman J, Brown B, Sauceda JA, Henley L, Deeks SG, Fox L, Gandhi R, Smith DM, Li J
Authors: Kirsten Bibbins-Domingo, PhD, MD, MAS; Alicia Fernandez, MD
Authors: Bibbins-Domingo K, Fernandez A.
Volume 185 of Issue 8 | Cell
Authors: Yen M, Ren J, Liu Q, Glassman CR, Sheahan TP, Picton LK, Moreira FR, Rustagi A, Jude KM, Zhao X, Blish CA, Baric RS, Su LL, Garcia KC
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.
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