Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19

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   Résumé scientifique

   Elevated levels of the pro-inflammatory cytokine Interleukin 21 (IL-21) contribute to the progression of autoimmune and inflammatory diseases by binding to its receptor (IL-21R) and activating detrimental signaling pathways in immune cells. Consequently, we developed a recombinant decoy receptor protein designed to competitively inhibit IL-21 binding to its receptor. Using the extracellular domain of IL-21R as a scaffold, five key binding-site residues (33, 38, 70, 94, and 130) were mutated with OSPREY software. Computational analyses with GROMACS selected the Q33S, E38D, M70T, L94N, and M130S mutant for its superior structural stability and high binding affinity to IL-21, with binding energ…

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   Résumé scientifique

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   Résumé scientifique

   Abstract Small protein ligands, such as miniproteins, have the potential to provide the efficient physiological transport and rapid clearance required for radioligand therapy. Yet, binders require single-digit nanomolar affinity for potent targeting and high stability for radiolabeling and physiological integrity. High-affinity and stable single-domain miniproteins are also modular candidates for multispecific applications in cell engagers and avid constructs. Previous work demonstrated computationally designed 40-amino acid β⍺ββ miniproteins as effective scaffolds for ligand discovery. Herein, to yield the desired single-digit nanomolar affinity for B7-H3, an important immune regulator and …

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   Résumé scientifique

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   Résumé scientifique

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   Résumé scientifique

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   Résumé scientifique

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   Résumé scientifique

   The therapeutic efficacy of protein biologics is often hampered by their rapid in vivo degradation and off-target effects. Interleukin-2 (IL-2), a cytokine promising for treating autoimmune diseases via regulatory T cell (Treg) expansion, exemplifies this challenge due to its short half-life and pleiotropic activity. Herein, we report a molecular-scale topology engineering strategy to overcome these limitations. By using split intein mediated ligation and genetically encoded entangling motif, p53dim (X), we constructed cyclic (c-IL-2) and catenated (cat-IL-2) variants of IL-2 via direct expression in E. coli. These topological proteins preserve the native conformation and receptor binding ca…