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32 The lack of tolerance of polar residues at this position was supported by an experiment replacing Ala with Val and led to only a marginal reduction in biological activity (3-fold)

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Classic examples include native GLP-1, which has a plasma half-life of approximately 2 minutes and required continuous infusion in early studiesan impractical route for chronic therapyyet was subsequently transformed into a once-weekly therapeutic through lipidation and albumin-binding strategies ( Third, pleiotropic signaling that aligns with physiological function rather than nonspecific toxicity favors re-evaluation