Semaglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist — a structural analogue of the endogenous incretin hormone GLP-1(7-36) amide. It was developed by researchers at Novo Nordisk and first described in the peer-reviewed literature in 2015.

What is the chemical structure of semaglutide?

Semaglutide is a 31-amino-acid polypeptide with a molecular formula of C₁₈₇H₂₉₁N₄₅O₅₉ and a molecular weight of approximately 4,114 daltons. Three structural modifications distinguish it from native GLP-1 — an Aib substitution at position 8, an Arg substitution at position 34, and a C18 fatty diacid moiety conjugated via a bifunctional linker at position 26.

Is semaglutide FDA approved?

Semaglutide has received multiple FDA approvals. A subcutaneous formulation was approved in December 2017 for glycemic management in type 2 diabetes; an oral tablet formulation was approved in September 2019 for the same indication; a higher-concentration subcutaneous formulation was approved in June 2021 for chronic weight management; and a cardiovascular risk-reduction indication was added following the SELECT trial in 2023.

Who discovered semaglutide?

Semaglutide was discovered by a research team at Novo Nordisk, with the synthesis and structure-activity characterization published in the Journal of Medicinal Chemistry in 2015 by Lau, Bloch, Schäffer, and colleagues. The scientific lineage traces to foundational GLP-1 work by Joel Habener, Svetlana Mojsov, and Jens Holst in the 1980s.

How does semaglutide differ from other GLP-1 receptor agonists?

Within the GLP-1RA class, semaglutide is distinguished by its high albumin-binding affinity — achieved through a C18 fatty diacid acyl side chain — which extends its terminal plasma half-life to approximately 165 hours and enables once-weekly administration. The earlier analogue liraglutide, by contrast, uses a C16 fatty acid moiety and has a half-life of approximately 13 hours.

Semaglutide: A Research Overview | SpartaLabs Research Library

Introduction

Semaglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist — a class of compound that mimics the activity of the endogenous incretin hormone GLP-1(7-36) amide at the GLP-1 receptor (GLP-1R). It was developed by a research team at Novo Nordisk and first described in the peer-reviewed literature in 2015 [1]. The compound is of scientific interest because of its extended plasma half-life relative to endogenous GLP-1, achieved through specific structural engineering, and because of an extensive body of published clinical evidence generated across the SUSTAIN, PIONEER, STEP, and SELECT trial programs.

Background

Glucagon-like peptide-1 was identified as a potent insulinotropic factor in studies conducted in the 1980s. Research published in 1987 by Mojsov and colleagues at the Massachusetts General Hospital reported that GLP-1(7-37), a cleavage product of proglucagon expressed in intestinal L-cells, stimulated insulin secretion from the perfused rat pancreas at picomolar concentrations [2]. Subsequent work established GLP-1(7-36) amide as the principal circulating form with incretin activity in humans [3]. A central limitation of endogenous GLP-1 as a therapeutic scaffold was its rapid proteolytic degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), which confers a plasma half-life of under two minutes [4].

Pharmaceutical programs at Novo Nordisk sought to design GLP-1 analogues with extended half-lives compatible with less frequent administration. An earlier compound, liraglutide — a once-daily GLP-1 analogue — introduced the strategy of fatty-acid acylation to promote reversible binding to serum albumin and reduce renal clearance [5]. Semaglutide represents an evolution of this approach, engineered specifically for once-weekly administration.

Chemistry and Structure

The primary structure and synthesis of semaglutide were described in detail by Lau, Bloch, Schäffer, Ursula Knudsen, and colleagues from Novo Nordisk in a 2015 publication in the Journal of Medicinal Chemistry [1]. The compound is a 31-amino-acid polypeptide analogue of human GLP-1(7-37).

Three key structural modifications distinguish semaglutide from native GLP-1. First, the alanine residue at position 8 is replaced by alpha-aminoisobutyric acid (Aib), a non-canonical amino acid that confers resistance to DPP-4 cleavage at the N-terminus [1]. Second, the lysine at position 34 is substituted with arginine [1]. Third, the lysine at position 26 is derivatized via a bifunctional linker — composed of two gamma-glutamic acid spacers and a mini-PEG chain — to a C18 fatty diacid moiety [1]. This acyl side chain facilitates tight, reversible binding to serum albumin, substantially reducing the rate of renal filtration and extending the terminal half-life to approximately 165 hours in humans, enabling a once-weekly administration interval [1].

The reported molecular formula is C₁₈₇H₂₉₁N₄₅O₅₉, with a molecular weight of approximately 4,114 daltons [1].

Pharmacological Classification

Semaglutide is classified as a glucagon-like peptide-1 receptor agonist (GLP-1RA). GLP-1Rs belong to the class B subfamily of G-protein-coupled receptors (GPCRs) — a structurally distinct family characterized by an extracellular N-terminal domain that participates in ligand recognition [4]. Mechanistic aspects of GLP-1R signaling are covered in the companion semaglutide mechanism-of-action article in this library.

Within the broader GLP-1RA class, semaglutide is distinguished by a high degree of albumin binding, high GLP-1R selectivity, and a once-weekly half-life profile [1]. It has been studied in subcutaneous injection and oral tablet formulations. The oral formulation co-formulates semaglutide with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), which facilitates gastric-epithelial absorption [6]. Researchers examining the GLP-1RA class from a structural perspective may also consult the Tirzepatide research overview, which covers a dual GIP/GLP-1 receptor agonist in the same pharmacological family.

Regulatory History

Semaglutide has received multiple FDA approvals across distinct formulations and indications, based on data from the company's clinical trial programs, representing one of the most fully characterized regulatory profiles in the GLP-1RA class.

A subcutaneous formulation received FDA approval in December 2017, for use as an adjunct to diet and exercise in adults with type 2 diabetes mellitus. An oral tablet formulation received FDA approval in September 2019, for the same glycemic management indication — the first oral GLP-1 receptor agonist to receive FDA authorization for any use. A higher-concentration subcutaneous formulation received FDA approval in June 2021, for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity, in combination with a reduced-calorie diet and physical activity. An additional cardiovascular risk-reduction indication was subsequently added following the SELECT trial, reported by Lincoff and colleagues in 2023 [7].

The regulatory chronology relevant to compounding: in February 2025, the FDA issued a declaratory order resolving the previously declared shortage of semaglutide injection products, with enforcement discretion periods for 503A and 503B compounding concluding in April and May 2025, respectively [8]. The full regulatory timeline is detailed in the companion history article in this library. Research-grade semaglutide from SpartaLabs is available with third-party-verified purity documentation for qualified research applications.

Discovery History

The scientific lineage of semaglutide traces to foundational work on the glucagon superfamily in the 1980s. Joel Habener and Svetlana Mojsov at Massachusetts General Hospital, and Jens Holst and colleagues in Denmark, independently identified the insulinotropic properties of GLP-1 cleavage products [2, 3]. Daniel Drucker's laboratory subsequently characterized the molecular control of proglucagon expression and the broader physiological role of GLP-1 [4].

Applied research at Novo Nordisk in the 1990s and 2000s — including work by Lotte Bjerre Knudsen, who later became chief scientific adviser at the company — focused on engineering GLP-1 analogues with extended pharmacokinetics. The liraglutide program, which introduced the albumin-binding fatty-acid strategy, preceded semaglutide and established the therapeutic viability of the approach [5]. The engineering principles and structure-activity relationships that produced semaglutide were described formally by Lau et al. in 2015 [1]. In 2024, Habener, Mojsov, and Knudsen received the Albert Lasker Award for Basic Medical Research in recognition of foundational contributions to the GLP-1 field [9].

References

Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370–7380. doi:10.1021/acs.jmedchem.5b00726. PubMed PMID: 26308095.
Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest. 1987;79(2):616–619. doi:10.1172/JCI112855. PubMed PMID: 3543057.
Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987;211(2):169–174. PubMed PMID: 2890903.
Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756. doi:10.1016/j.cmet.2018.03.001. PubMed PMID: 29617641.
Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019;10:155. doi:10.3389/fendo.2019.00155. PubMed PMID: 30915025. PMC6474072.
Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841–851. doi:10.1056/NEJMoa1901118. PubMed PMID: 31185157.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563. PubMed PMID: 37952131.
U.S. Food and Drug Administration. Declaratory Order: Resolution of Shortages of Semaglutide. February 2025. Available at: https://www.fda.gov/media/185526/download
Albert and Mary Lasker Foundation. 2024 Lasker Awards. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11446598/ (PMC commentary, PubMed PMID: 39352127).