Weekly Revolution: Unveiling the Science Behind Semaglutide

The Weekly Revolution: Unveiling the Science Behind Semaglutide's Discovery

The story of GLP-1 (Glucagon-Like Peptide-1) is one of continuous scientific refinement. After the success of liraglutide, the first once-daily GLP-1 analogue that revolutionized diabetes management and showed significant weight loss benefits, the scientific community, particularly at Novo Nordisk, set its sights on an even more ambitious goal: a once-weekly GLP-1 analogue.

Why once weekly? 

Patient convenience is key. A single weekly injection would drastically improve adherence and quality of life compared to daily shots. But achieving this meant pushing the boundaries of molecular engineering even further. The challenge was immense: the new analogue needed not only to be highly potent at activating the GLP-1 receptor but also to possess exceptionally long-lasting action in the body, enduring metabolic breakdown for an entire week.

This monumental task was meticulously detailed in a 2015 landmark paper published in the Journal of Medicinal Chemistry, titled "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide." The lead authors, Jesper Lau, Lotte Bjerre Knudsen, and their extensive team at Novo Nordisk, unveiled the precise molecular innovations that led to this breakthrough.

The Scientific Quest for a Once-Weekly GLP-1

Building upon the success of liraglutide (which achieved once-daily dosing by binding to serum albumin via a C16 fatty acid), the team knew that for once-weekly action, they needed to achieve:

1. Even Higher Albumin Affinity: The drug had to bind much more strongly and for longer to serum albumin, protecting it from breakdown and prolonging      its circulation.
2. Full Metabolic Stability: It needed to be fully resistant to the primary enzymes that degrade GLP-1, especially DPP-IV (dipeptidyl peptidase IV),      and also stable against other enzymes like neutral endopeptidase (NEP).

To achieve this, the researchers embarked on a systematic process of designing and testing a vast array of modified GLP-1 molecules. Their strategy involved two main types of modifications:

• Amino Acid Substitutions: They made changes to the original GLP-1 amino acid sequence to enhance stability.
• Acylation (Fatty Acid Attachment): They modified the GLP-1 molecule by attaching various fatty acid derivatives, which was crucial for controlling albumin binding and half-life. They also carefully considered the "linking chemistry" – how the fatty acid was attached to the peptide.

How Semaglutide's Specific Sequence Was Finalized

Through painstaking design, synthesis, and evaluation, the team systematically explored thousands of possibilities. The process involved precise "structure-activity relationship" (SAR) studies, where they tweaked one part of the molecule at a time and observed the effect on potency, stability, and binding.

Semaglutide emerged as the optimal candidate due to a very specific and carefully chosen combination of modifications:

        1. Amino Acid Substitutions:

• Aib8 (alpha-aminoisobutyric acid at position 8): This was a critical substitution. The original Alanine at position 8 (Ala8) in GLP-1 is a prime target for the DPP-IV enzyme, which quickly chops the peptide and inactivates it. Replacing Ala8 with Aib8 created a steric hindrance (a kind of molecular "shield") that made Semaglutide completely resistant to DPP-IV degradation. This was a foundational step for long-term stability.
• Arg34 (Arginine at position 34): This substitution replaced a Lysine at position 34. While the paper mentions other Lysine replacements were       tested, Arg34 was chosen as it provided a suitable attachment point for the fatty acid chain that would enhance albumin binding without       compromising potency.

       2. Acylation – The Long-Acting Tail:

• Lysine 26 as the Attachment Site: The fatty acid was specifically attached to Lysine at position 26.
• C18 Diacid and Short PEG Linker: This was the crucial innovation for once-weekly dosing. Instead of a C16 monoacid like in liraglutide, Semaglutide features a C18 diacid (octadecanedioic acid). This means it's an 18-carbon fatty acid with two carboxylic acid groups. This diacid, connected via a short polyethylene glycol (PEG) linker, played a critical role in increasing albumin affinity dramatically. The PEG linker adds flexibility and solubility, further enhancing the       interaction with albumin and the overall pharmacokinetic profile.

The combined effect of these precise modifications was remarkable:

• High GLP-1 Receptor Affinity: Semaglutide maintained a very high potency at the GLP-1 receptor, comparable to or even slightly better than native      GLP-1.
• Full Metabolic Stability: Thanks to the Aib8 substitution, it was fully stable against DPP-IV degradation.
• Extremely High Albumin Binding: The C18 diacid and PEG linker ensured exceptionally strong binding to serum albumin, leading to a significantly      prolonged half-life.

These properties collectively made Semaglutide an ideal candidate for once-weekly subcutaneous administration, as demonstrated by its preclinical data.

What Was Still Missing (and What Came Next)

The 2015 paper was a "discovery" paper, focusing on the chemical synthesis and characterization of the Semaglutide molecule and its preclinical (laboratory and animal) properties. While it confidently concluded that Semaglutide was an "optimal once weekly candidate" with "pharmacokinetic properties suitable for once-weekly administration," several crucial steps were still "missing" from a therapeutic perspective:

1. Extensive Human Clinical Trials: The true efficacy and safety in human patients with type 2 diabetes and obesity needed to be rigorously tested in large-scale Phase 1, 2, and 3 clinical trials. This is where the observed preclinical benefits would be confirmed (or not) in diverse patient populations.
2. Long-Term Safety Data: While preclinical studies provide clues, long-term safety and tolerability in humans are paramount and can only be assessed through years of clinical trials and post-market surveillance.
3. Regulatory Approval: Even after successful trials, the drug would need to go through the rigorous approval processes of regulatory bodies like the FDA (U.S.) and EMA (Europe) before it could reach patients.
4. Optimal Dosing Regimens: While the paper suggested once weekly, the exact therapeutic doses for different indications (diabetes vs. obesity) would      need to be meticulously determined in human trials.

Indeed, the years following this 2015 discovery paper saw the successful completion of these "missing" steps. Semaglutide went on to be approved as Ozempic® for type 2 diabetes (first approved in 2017 in the US) and later as Wegovy® for obesity (approved in 2021 in the US), fulfilling the promise of a highly effective once-weekly GLP-1 analogue. Its success has since spurred further research, leading to even more potent compounds like dual and triple agonists, showing that the quest for improved metabolic treatments continues.