The Origin of GLP-1 Drug Peptides

In the 1960s, scientists discovered human GLP-1 receptor agonists. GLP-1 is an intestinal

peptide hormone secreted by L-cells of the small intestinal mucosa. It acts on receptors in specific areas of the brain to efectively inhibit the appetite center, enhance satiety, andreduce food intake5 . GLP-1 regulates glucose metabolism through multiple mechanisms to achieve blood sugar control and weight loss.

Figure 1: Biological efects of GLP-1 on target tissues

(Source: Frontiers in Endocrinology)

Initially known primarily as a blood sugar regulator, GLP-1 is now recognized for its roles in treating diabetes, cardiovascular disease, Alzheimer’s, depression, kidney and liver diseases, and arthritis.

 

Liraglutide

Because the plasma half-life of natural human GLP-1 is extremely short (less than 2 minutes), scientists began developing long-acting GLP-1 analogues. In the early 21st century, the Danish company Novo Nordisk successfully developed Liraglutide, a peptide drug with 97% homology to human GLP-1. It was approved in the EU and US in 2009 and 2010 respectively, and launched in China in 2011.

Figure 2: Structural formula of Liraglutide

The N-terminal sequence of natural GLP-1 (His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu...) (7-36 amide) contains a key cleavage site: Ala-Glu. This site is specifically recognized by the DPP-4 enzyme, which hydrolyzes and removes the first 8 amino acids. This process transforms active GLP-1 into an inactive fragment, resulting in its short half-life. Furthermore, the wide distribution of DPP-4 in vascular endothelial cells and lymphocytes accelerates its clearance, making natural GLP-1 dificult to use clinically.

Figure 3: DPP-4 cleavage site on GLP-1

(Source: Frontiers in Endocrinology)

Liraglutide’s design achieved two breakthroughs:

1.   Palmitic Acid Side Chain: A 16-carbon fatty acid allows it to bind reversibly to serum albumin, protecting it from DPP-4 degradation.

2.  Amino Acid Modification: Replacing Lysine at position 34 with Arginine enhanced structural stability.

These modifications extended the half-life to approximately 13 hours, allowing for once- daily subcutaneous injection.

Therapeutic Efects:

•     Pancreas: Promotes glucose-dependent insulin secretion and protects β-cells.

    •     CNS: Activates satiety signals in the hypothalamus and reduces cravings for high- calorie foods.

•     Gastrointestinal: Delays gastric emptying.

•     Cardiovascular: Improves endothelial function and inhibits atherosclerosis.

•     Metabolism: Promotes "browning" of white fat and improves liver insulin sensitivity.

Semaglutide

Building on Liraglutide’s success, Novo Nordisk developed Semaglutide, a next-generation GLP-1 analogue with 94% sequence homology. It targets type 2 diabetes and obesity with a significantly longer half-life of approximately 7 days, allowing for once-weekly injections.

Unlike many drugs, its metabolism is widespread across tissues rather than being confined to specific organs, meaning its use is not limited by liver or kidney function.

Drug Name

Long-acting Strategy

Half-life

 

Exenatide

Sustained-release microspheres; sequence modification

2.5 hours

 

Beinaglutide

PEGylation (Polyethylene glycol chain)

4 days

 

Dulaglutide

Fc fusion protein (Immunoglobulin)

4.7 days

 

Semaglutide

Fatty diacid side chain; amino acid substitution

7 days

 

Glutazumab (Phase III)

GLP-1 peptide fused with GLP-1R antibody

1 month

Table 1: Long-acting Strategies for GLP-1RA Drugs

(Source: Chinese Prescription Drugs)

Semaglutide is composed of a total of 31 amino acids consisting of 17 distinct types. These 17 amino acids are: histidine, alpha-aminoisobutyric acid, glutamic acid, glycine, threonine, phenylalanine, serine, aspartic acid, valine, tyrosine, leucine, glutamine,

alanine, lysine, isoleucine, tryptophan, and arginine.

Structural Modification and Synthesis

 

 

•     Modification Structure: The lysine residue of semaglutide contains a C18 fatty diacid modification.

•     Spacer Modification: Between the lysine and this modification structure, there is a spacer composed of glutamic acid and a 2-[2-(2-aminoethoxy)ethoxy]acetic acid dimer4 .

•     Synthesis Method: During the synthesis of semaglutide, the peptide backbone and the side chain containing the C18 fatty diacid are generally synthesized separately and then conjugated.

•     Fragment Assembly: The entire molecule is assembled from multiple fragments combined together.

Semaglutide features three critical modifications:

1.  Aib Substitution: Alanine at position 8 is replaced by α-aminobutyric acid to "hide" the cleavage site from DPP-4.

2.  Arg Substitution: Lysine at position 34 is replaced by Arginine.

3.  C18 Side Chain: Lysine at position 26 is acylated with an 18-carbon fatty diacid and a 2xOEG spacer, allowing for tighter binding to plasma albumin and reduced renal

filtration.

Figure 4: Simplified structure of Semaglutide

Through these ingenious modifications, the drug's half-life can be extended to approximately 7 days.

Figure 5: (A) Crystal structure of the semaglutide peptide backbone (gray) complexed

with the GLP-1 receptor extracellular domain (gold surface); (B, C) Magnified overall

structure.

(Source: Frontiers in Endocrinology)

 

Tirzepatide

Following Liraglutide and Semaglutide, the field of GLP-1 receptor agonists (GLP-1RAs) has seen a new breakthrough: Tirzepatide. Developed by the American company Eli Lilly,

Tirzepatide is a dual agonist for both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor. The drug received approval from both the US FDA  and the European Union in 2022 for the treatment of type 2 diabetes, demonstrating

significant glucose-lowering and weight-loss efects in multiple clinical trials.

Tirzepatide is an engineered 39-amino acid peptide with a structure based on the GIP

sequence, achieving long-acting properties through a C20 fatty acid side chain. Unlike

pure GLP-1 receptor agonists, Tirzepatide activates two types of receptors simultaneously to create a synergistic efect:

•     GIP Receptor Activation: Enhances insulin secretion, improves insulin sensitivity, and may promote lipid metabolism.

•     GLP-1 Receptor Activation: Inhibits appetite, delays gastric emptying, and promotes insulin secretion.

Figure 6: Key milestones in Tirzepatide treatment for type 2 diabetes

(Source: Springer Nature)

This dual-agonist mechanism allows it to outperform single GLP-1 receptor agonists in both blood sugar control and weight reduction. Tirzepatide has a half-life of approximately 5

days, supporting once-weekly subcutaneous injections.

In several Phase III clinical trials (such as the SURPASS series), Tirzepatide was significantly superior to Semaglutide and insulin in reducing glycated hemoglobin (HbA1c) and body

weight. Some patients experienced a weight loss of over 20%, making it one of the most potent weight-loss medications currently available.

 

Tirzepatide is currently available in an injectable format. Its common adverse reactions are similar to other GLP-1 drugs, primarily consisting of gastrointestinal issues (nausea,

diarrhea, vomiting, etc.), which are mostly mild to moderate and typically decrease over  time. Due to its dual-receptor mechanism, more real-world data is still needed to support its long-term safety.

Tirzepatide represents a new generation of dual-target GLP-1/GIP drugs, ofering a new

treatment option for patients with type 2 diabetes and obesity. In the future, with the

development of oral formulations and the expansion of approved indications, Tirzepatide is expected to play an even more significant role in metabolic disease treatment.

Translation of Figure 8:

Mechanism of Oral Semaglutide Absorption

1.  Gastric Erosion: The oral formulation composed of Semaglutide and SNAC enters the stomach and is rapidly eroded by gastric juice.

2.   Drug Release and Protection: The release of a large amount of SNAC leads to a  local rise in pH, which reduces the activity of pepsin. Simultaneously, it disperses the micellar Semaglutide, making it more favorable for absorption.

3.  Absorption: SNAC is incorporated into the lipid membrane, reversibly increasing the fluidity of the gastric epithelial membrane. This allows the Semaglutide to be absorbed into the body and enter the systemic circulation.

Semaglutide's impact on weight loss is particularly significant; clinical practice has shown it delays gastric emptying, increases satiety, and reduces appetite. The weight-loss-

specific version, Wegovy, was approved by the US FDA in June 2021 for once-weekly 2.4 mg subcutaneous injections.

However, there are specific criteria for its use:

•     BMI > 30 (Obese)

•    BMI 27–30 with at least one weight-related comorbidity

Even with proper use, side efects cannot be ignored; the reported rate of gastrointestinal

adverse events in clinical trials for Wegovy reached 84.1%, including nausea, diarrhea, and