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Semaglutide (Molecule of the Month for March 2021)

Ozempic, Rybelsus

Semaglutideis currently sold as an anti-diabetic medication used for the treatment of type 2 diabetes. New discovery though means that it could be used as an appetite reduction drug to tackle obesity. Semaglutide acts like human glucagon-like peptide-1 (GLP-1) so that it increases insulin production, which in turn increases sugar metabolism. It is distributed as a metered subcutaneous injection in a prefilled pen - trade name Ozempic available from 2017, or very recently as a pill in 2020 with trade name Rybelsus. One of its advantages over other antidiabetic drugs is that it has a long duration of action, thus, only once-a-week injection is sufficient.

As a drug that suppresses appetite, Semaglutide has led to some people losing more than a fifth of their body weight, a major international trial shows. A weekly injection of the drug, semaglutide, was given alongside advice on diet and fitness.The study, conducted on almost 2,000 people, showed an average 15kg weight loss during the 15-month trial. The trial gave some people the drug and others a dummy injection, while both groups were given the lifestyle advice. The results, published in the New England Journal of Medicine, showed people lost an average of 15kg on semaglutide compared with 2.6kg without. However, 32% of people lost a fifth of their body weight with the drug, compared with fewer than 2% on the dummy treatment.

Picture of Semaglutide 3D model

Semaglutide is chemically similar to human produced amino acid peptide called glucagon-like peptide-1 (GLP-1). This peptide has a long chain helix shape, shown in the image as a red spiral. The only differences are two amino acid substitutions at positions 8 and 34, where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine respectively. Amino acid substitution at position 8 prevents chemical breakdown by an enzyme dipeptidyl peptidase-4. In addition, lysine at position 26 is in its derivative form (acylated with stearic diacid). Acylation with a spacer and C-18 fatty diacid chain increases the drug binding to blood protein (albumin), which enables longer presence in the blood circulation.

Picture of Semaglutide 3D model

Semaglutide is a glucagon-like peptide-1 receptor agonist. It increases the production of insulin, a hormone that lowers the blood sugar level. It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production. On the other hand it inhibits glucagon, which is a hormone that increases blood sugar. It additionally reduces food intake by lowering appetite and slows down digestion in the stomach. In this way it works in body fat reduction.

Picture of Semaglutide 3D model

click on the picture of  Semaglutide above to interact
with the 3D model of the
Semaglutide structure
(this will open a new browser window)

Picture of Semaglutide

C187 H291 N45 O59

Update by Karl Harrison
(Molecule of the Month for March 2021 )

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