Miniprotein engineering for inhibition of PD-1/PD-L1 interaction.

Autor: Ciesiołkiewicz A; Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland., Lizandra Perez J; Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland., Skalniak L; Faculty of Chemistry, Jagiellonian University, Kraków, Poland., Noceń P; Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland., Berlicki Ł; Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2024 Aug; Vol. 33 (8), pp. e5106.
DOI: 10.1002/pro.5106
Abstrakt: Miniproteins constitute an excellent basis for the development of structurally demanding functional molecules. The engrailed homeodomain, a three-helix-containing miniprotein, was applied as a scaffold for constructing programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) interaction inhibitors. PD-L1 binders were initially designed using the computer-aided approach and subsequently optimized iteratively. The conformational stability was assessed for each obtained miniprotein using circular dichroism spectroscopy, indicating that numerous mutations could be introduced. The formation of a sizable hydrophobic surface at the inhibitor that fits the molecular target imposed the necessity for the incorporation of additional charged amino acid residues to retain its appropriate solubility. Finally, the miniprotein effectively binding to PD-L1 (K D  = 51.4 nM) that inhibits PD-1/PD-L1 interaction in cell-based studies with EC 50  = 3.9 μM, was discovered.
(© 2024 The Protein Society.)
Databáze: MEDLINE
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