GLP-1 S — Published Research

GLP-1 S incorporates a C-18 fatty di-acid chain (octadecanedioic acid) attached to lysine at position 26 via a mini-PEG linker (γGlu-2×OEG spacer). This acyl moiety binds non-covalently to serum albumin with high affinity, creating a circulating depot that shields the peptide from renal clearance and enzymatic degradation. The resulting structural profile reflects the compound’s modified acylation strategy. The spacer length and fatty acid chain were specifically optimized to balance albumin binding strength with receptor accessibility. For laboratory research use only.

Citation: Lau J, Bloch P, Schäffer L, et al. “Discovery of the Long-Acting Glucagon-Like Peptide-1 (GLP-1) Analogue GLP-1 S.” J Med Chem. 2015;58(18):7370-7380. PubMed

GLP-1 S shares 94% amino acid sequence homology with endogenous human GLP-1(7-37), differing at only two positions. An α-aminoisobutyric acid (Aib) substitution at position 8 confers resistance to dipeptidyl peptidase-4 (DPP-4) cleavage, which normally inactivates native GLP-1 within 2-3 minutes. Arginine replaces lysine at position 34 to prevent unwanted fatty acid conjugation at that site, directing acylation exclusively to Lys26. These minimal modifications preserve full GLP-1 receptor binding potency while dramatically extending the molecule’s circulating persistence. For laboratory research use only.

Citation: Lau J, Bloch P, Schäffer L, et al. “Discovery of the Long-Acting Glucagon-Like Peptide-1 (GLP-1) Analogue GLP-1 S.” J Med Chem. 2015;58(18):7370-7380. PubMed

GLP-1 S is a selective GLP-1 receptor agonist with no meaningful affinity for the GIP receptor, glucagon receptor, or other class B GPCRs. In radioligand binding assays, GLP-1 S displaces GLP-1 from its receptor with an IC₅₀ comparable to native GLP-1, demonstrating preserved binding potency despite structural modifications. The Aib8 substitution and C-18 fatty di-acid acylation do not substantially alter receptor binding affinity or cAMP generation efficacy at GLP-1R. This selectivity profile distinguishes GLP-1 S from multi-receptor agonists such as GLP-2 T. For laboratory research use only.

Citation: Lau J, Bloch P, Schäffer L, et al. “Discovery of the Long-Acting Glucagon-Like Peptide-1 (GLP-1) Analogue GLP-1 S.” J Med Chem. 2015;58(18):7370-7380. PubMed

GLP-1 S’s design followed systematic structure-activity relationship studies starting from liraglutide (C-16 acyl chain, once-daily). Researchers evaluated fatty acid chain lengths (C-16 to C-20), spacer compositions (γGlu, OEG combinations), and acylation positions to optimize the balance between albumin binding affinity, GLP-1R potency, and pharmacokinetic half-life. The C-18 di-acid with γGlu-2×OEG spacer at Lys26 yielded the optimal profile: 3-fold stronger albumin affinity than liraglutide while maintaining equivalent receptor activation potency. Over 50 analogs were synthesized and characterized during this optimization process. For laboratory research use only.

Citation: Lau J, Bloch P, Schäffer L, et al. “Discovery of the Long-Acting Glucagon-Like Peptide-1 (GLP-1) Analogue GLP-1 S.” J Med Chem. 2015;58(18):7370-7380. PubMed