GLP-1S (Semaglutide): Chemistry Profile & Research Overview

What Is GLP-1S?

GLP-1S is a synthetic 31-amino-acid peptide assigned CAS number 910463-68-2, also known by the chemical name semaglutide and the development code NN9535. It is an analog of glucagon-like peptide-1 (GLP-1), an endogenous mammalian incretin peptide derived from the proglucagon precursor. Structurally, GLP-1S differs from native GLP-1(7-37) by two engineered modifications: substitution of alanine at position 2 with alpha-aminoisobutyric acid (Aib), and attachment of a C18 dicarboxylic fatty acid chain at Lys26 via a gamma-glutamyl-2x(2-(2-aminoethoxy)ethoxy)acetyl (gamma-Glu-2xOEG) spacer. The Aib-2 substitution confers resistance to N-terminal cleavage by dipeptidyl peptidase-4 (DPP-4), while the lipidation enables non-covalent binding to serum albumin in research matrices — a recognized methodology for extending the circulating half-life of small peptides. As a research-grade synthetic peptide, GLP-1S is widely used in vitro and in non-human systems as a model substrate in peptide stability research, in lipidated SPPS methodology, and as a reference compound in class-B GPCR pharmacology screens.

Chemical Properties

Historical Development and Discovery

The GLP-1S sequence was developed in the late 2000s and early 2010s as part of a systematic structure-activity research program investigating long-acting analogs of glucagon-like peptide-1. Native GLP-1 had been characterized as a 30-residue proglucagon-derived peptide secreted from intestinal L-cells, but its very short plasma half-life in research models — on the order of 1–2 minutes — limited its experimental utility. Investigators at Novo Nordisk built on prior work with liraglutide (a C16 acylated analog) and systematically varied the fatty acid chain length, the spacer chemistry, and the position-2 residue to identify a profile with substantially extended half-life. The Aib-2 substitution together with a C18 diacid attached via a double-OEG spacer produced the most favorable albumin-binding profile in published in vitro work. The compound entered the chemical literature under the development code NN9535 and the INN semaglutide. It has since become a standard reference compound in lipidated peptide methodology and class-B GPCR ligand research.

Chemical Architecture and Structural Features

The Aib-2 Substitution and DPP-4 Resistance

The first defining modification of GLP-1S is the substitution at position 2: native GLP-1(7-37) carries an alanine at this position, which is recognized by DPP-4 as the second residue of an X-Ala dipeptide motif. Replacement with alpha-aminoisobutyric acid (Aib) — a non-natural amino acid with two methyl groups on the alpha-carbon — sterically blocks DPP-4 recognition. The Aib substitution is a well-established strategy in incretin medicinal-chemistry research and is preserved in several related analogs.

The Lipidation Strategy and Albumin Binding

The second defining modification is the attachment of a C18 dicarboxylic fatty acid chain (1,18-octadecanedioic acid) to the epsilon-amine of Lys26 via a hydrophilic gamma-glutamyl-2xOEG spacer. The fatty acid chain binds non-covalently to plasma albumin in research matrices, depoting the peptide and shielding it from renal clearance and proteolytic degradation. The double-OEG spacer was selected for its balance of conformational flexibility and aqueous solubility. This lipidation strategy is now a textbook example of half-life extension by albumin tethering.

Solid-Phase Synthesis Considerations

GLP-1S is produced by Fmoc-based solid-phase peptide synthesis (SPPS) with side-chain protection on Lys26 to permit selective post-assembly attachment of the spacer-lipid moiety. Common challenges discussed in the synthesis literature include aspartimide formation at Asp-Gly junctions, methionine oxidation during global deprotection, and yield optimization of the gamma-Glu-2xOEG-C18 conjugation step. These are addressed through standard pseudoproline, protecting-group, and scavenger strategies.

Research Mechanisms

In published in vitro and non-human research, GLP-1S has been characterized as a receptor agonist at the GLP-1 receptor (a class-B G-protein-coupled receptor) with substantially extended biochemical half-life relative to native GLP-1 in DPP-4-containing matrices and in albumin-containing buffers. This profile makes it a useful comparator in pharmacology screens of lipidated peptides, in receptor-binding methodology research, in protease-stability assays, and in albumin-binding characterization studies. ITide Labs supplies GLP-1S as a research-grade reference standard for these applications.

Research Areas

• Lipidated peptide stability and protease-resistance methodology research
• Solid-phase peptide synthesis of side-chain-modified peptides
• Albumin-binding and half-life extension methodology
• Class-B GPCR receptor-binding and pharmacology research
• Reference standard in analytical method development (HPLC-UV, LC-MS)
• Comparative structure-activity research on the incretin peptide family

Quality Assurance

ITide Labs releases each lot of GLP-1S against an independent third-party Certificate of Analysis. Lot-specific COAs are published on the corresponding product page once analysis is complete. Identity is confirmed by LC-MS, purity by RP-HPLC-UV, and endotoxin levels by kinetic chromogenic LAL assay. Lyophilized material is stored at 2–8 °C protected from light and is supplied with batch-specific documentation.

Frequently Asked Questions

What is the CAS number for GLP-1S?

The CAS number for GLP-1S (semaglutide) is 910463-68-2.

What is the molecular weight of GLP-1S?

The monoisotopic molecular weight of GLP-1S is 4113.58 g/mol. The empirical formula is C₁₈₇H₂₉₁N₄₅O₅₉.

How many amino acids are in GLP-1S?

GLP-1S contains 31 amino acid residues in the peptide backbone, plus an attached C18 dicarboxylic fatty acid moiety conjugated via a gamma-glutamyl-2xOEG spacer at Lys26.

How does GLP-1S differ from native GLP-1?

GLP-1S differs from native human GLP-1(7-37) by two modifications: alanine at position 2 is replaced with alpha-aminoisobutyric acid (Aib), and Lys26 carries a C18 fatty acid chain attached via a gamma-glutamyl-2xOEG spacer. These changes confer DPP-4 resistance and enable albumin binding in research matrices.

What is the development code for GLP-1S?

GLP-1S was developed under the code NN9535 by Novo Nordisk. The INN is semaglutide.

What is the role of the C18 fatty acid chain in GLP-1S?

The C18 dicarboxylic fatty acid attached at Lys26 binds non-covalently to plasma albumin in research matrices, providing a depot effect that extends the biochemical half-life of the peptide. This is a recognized methodology for engineering long-acting synthetic peptides.

Why is GLP-1S used in research?

GLP-1S is used as a reference standard in lipidated peptide methodology, in protease-stability assays, in class-B GPCR receptor-binding studies, and in albumin-binding characterization research.

What laboratory storage does GLP-1S require?

Lyophilized GLP-1S should be stored at 2–8 °C protected from light for short-term storage and at –20 °C for long-term storage. Reconstituted solutions should be aliquoted and stored frozen.

Is GLP-1S available in different sizes from ITide Labs?

ITide Labs currently supplies GLP-1S as a 30 mg lyophilized lot. Lot-specific Certificates of Analysis are published on the product page once independent third-party characterization is complete.

Citation

ITide Labs. GLP-1S (Semaglutide): Chemistry Profile and Research Overview. Las Vegas, NV: ITide Labs LLC; 2026.