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Three modifications work in combination — Aib8 substitution eliminates DPP-IV cleavage at position 8, Arg34Lys substitution removes a proteolytic cleavage site, and the C18 fatty diacid conjugated via a hydrophilic mini-PEG linker at Lys26 enables tight reversible albumin binding that shields Semaglutide from proteolytic degradation and renal clearance, producing the approximately one-week half-life through albumin’s own pharmacokinetics
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