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Cells were incubated with QIs or parent compounds for 2.5 h, based on the time-dependency of QIs-induced loss of cell viability (Supplementary Figure S3)

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Semaglutide (Ozempic, Wegovy): GLP-1 receptor agonist 31-amino acid peptide Position 2: Aib substitution Position 20: Lys acylated with a C18 fatty diacid via a Glu-(AEEA-AEEA) linker Position 28: Arg substitution Tirzepatide (Mounjaro, Zepbound): Dual GIP/GLP-1 receptor agonist 39-amino acid peptide: Position 2 and 13: Aib substitution Position 20: Lys acylated with a C20 fatty diacid via a Glu-(AEEA-AEEA) linker Position 30-39: Amino acid sequence from exenatide Retatrutide: Triple GLP-1/GIP/GCG receptor agonist 39-amino acid peptide: Position 2 and 20: Aib substitution Position 13: Leucine modified with an -methyl group (2-Methylleucine) Position 17: Lys acylated with a C20 fatty diacid via a Glu-(AEEA) linker Position 30-39: Amino acid sequence from exenatide Semaglutide and Tirzepatide are widely available and well-studied, while Retatrutide's long-term effectiveness and safety profile are still being investigated in clinical trials

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