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A series of fatty chain-modified GLP-1 conjugates were designed and evaluated. Most compounds exhibited enhanced plasma stability in vitro. Importantly, 14 showed favorable long-acting glucose-lowering effect in diabetic mice.A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides (1–11) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Peptides 1, 6, 9, and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly8-GLP-1(7-36)-NH2 were selected for second step modifications to yield conjugates 12–23. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable compound 14 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of compound 14 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. Our results suggest that compound 14 is a promising type 2 antidiabetic agent deserving further investigation.