Cheaper, faster method produces 10x more

Manufacturing the groundbreaking and extremely popular diabetes and weight-loss drug semaglutide – Ozempic, Wegovy – is a complex, slow process. Amid ongoing global shortages, researchers have developed a cheaper, faster method that produces ten times more of a therapeutically similar version of the in-demand drug.

The effectiveness of semaglutide, sold as the diabetes drug Ozempic and weight-loss drug Wegovy, contributed to its overwhelming popularity and huge demand. This led to global shortages throughout 2022–23, which maker Novo Nordisk says will likely continue into this year. The shortage has particularly affected type 2 diabetics who rely on semaglutide to keep their blood glucose levels under control and are left searching for suitable alternatives.

Researchers at The Florey Institute in Melbourne, Australia, may have discovered a way of addressing the critical shortage, developing a method of production of a drug analog that has the same therapeutic effects as semaglutide. Their novel production method is not only cost-effective and simpler but produces far more of the drug.

“The method we’ve developed has fewer chemical steps and better yield that the current process for making semaglutide,” said Chaitra Chandrashekar, lead author of the study outlining the researchers’ novel drug production process. “Although more research is needed, it appears to be a way to rapidly and easily synthesize new drugs like semaglutide, while retaining their major therapeutic benefits.”

Semaglutide is part of the glucagon-like peptide-1 (GLP-1) family of drugs that mimic a naturally occurring hormone, lowering blood glucose and promoting weight loss. However, the drug’s chemical structure holds it back in terms of its production. One of its components is not easily dissolvable in water, making handling and large-scale purification and manufacture of semaglutide difficult. Which explains why the drug’s supplier has been unable to keep up with growing demand.

“We set out to develop an improved and cost-efficient synthetic process for making a potential new drug to target the GLP-1 receptor,” said Akhter Hossain, the study’s corresponding author. “Semaglutide has a very ‘hydrophobic’ component in its structure, meaning it’s not easily dissolved in water.”

Without getting too technical, semaglutide is produced by first engineering yeast cells to make peptides, chains of amino acids that form the drug’s ‘backbone.’ A modification is made by adding a fatty acid chain to improve the drug’s half-life in the blood, a process called lipidation. But it’s the added fatty acid that is the troublesome hydrophobic component.

Instead of using lipidation, Florey researchers used a process called glycosylation, the attachment of carbohydrate-based molecules (glycans) to the peptide surface. Using this approach produced a novel water-attracting – hydrophilic – analog of GLP-1 in far greater amounts.

“Glycosylation resulted in tenfold higher yields compared with semaglutide,” Hossain said.

In chemistry, an analog is a compound that’s structurally similar to another but varies slightly in composition. Importantly, the GLP-1 analog produced the same therapeutic effects as semaglutide.

“Our short-term experiments in animal models showed our potential drug performed as semaglutide would,” said Chandrashekar. “It significantly lowered blood glucose levels and promoted enhanced glucose disposal. Although more research is needed, it appears to be a way to rapidly and easily synthesize new drugs like semaglutide, while retaining their major therapeutic benefits for blood glucose control.”

The study was published in the Journal of Medicinal Chemistry.

Source: The Florey Institute

Manufacturing the groundbreaking and extremely popular diabetes and weight-loss drug semaglutide – Ozempic, Wegovy – is a complex, slow process. Amid ongoing global shortages, researchers have developed a cheaper, faster method that produces ten times more of a therapeutically similar version of the in-demand drug.

The effectiveness of semaglutide, sold as the diabetes drug Ozempic and weight-loss drug Wegovy, contributed to its overwhelming popularity and huge demand. This led to global shortages throughout 2022–23, which maker Novo Nordisk says will likely continue into this year. The shortage has particularly affected type 2 diabetics who rely on semaglutide to keep their blood glucose levels under control and are left searching for suitable alternatives.

Researchers at The Florey Institute in Melbourne, Australia, may have discovered a way of addressing the critical shortage, developing a method of production of a drug analog that has the same therapeutic effects as semaglutide. Their novel production method is not only cost-effective and simpler but produces far more of the drug.

“The method we’ve developed has fewer chemical steps and better yield that the current process for making semaglutide,” said Chaitra Chandrashekar, lead author of the study outlining the researchers’ novel drug production process. “Although more research is needed, it appears to be a way to rapidly and easily synthesize new drugs like semaglutide, while retaining their major therapeutic benefits.”

Semaglutide is part of the glucagon-like peptide-1 (GLP-1) family of drugs that mimic a naturally occurring hormone, lowering blood glucose and promoting weight loss. However, the drug’s chemical structure holds it back in terms of its production. One of its components is not easily dissolvable in water, making handling and large-scale purification and manufacture of semaglutide difficult. Which explains why the drug’s supplier has been unable to keep up with growing demand.

“We set out to develop an improved and cost-efficient synthetic process for making a potential new drug to target the GLP-1 receptor,” said Akhter Hossain, the study’s corresponding author. “Semaglutide has a very ‘hydrophobic’ component in its structure, meaning it’s not easily dissolved in water.”

Without getting too technical, semaglutide is produced by first engineering yeast cells to make peptides, chains of amino acids that form the drug’s ‘backbone.’ A modification is made by adding a fatty acid chain to improve the drug’s half-life in the blood, a process called lipidation. But it’s the added fatty acid that is the troublesome hydrophobic component.

Instead of using lipidation, Florey researchers used a process called glycosylation, the attachment of carbohydrate-based molecules (glycans) to the peptide surface. Using this approach produced a novel water-attracting – hydrophilic – analog of GLP-1 in far greater amounts.

“Glycosylation resulted in tenfold higher yields compared with semaglutide,” Hossain said.

In chemistry, an analog is a compound that’s structurally similar to another but varies slightly in composition. Importantly, the GLP-1 analog produced the same therapeutic effects as semaglutide.

“Our short-term experiments in animal models showed our potential drug performed as semaglutide would,” said Chandrashekar. “It significantly lowered blood glucose levels and promoted enhanced glucose disposal. Although more research is needed, it appears to be a way to rapidly and easily synthesize new drugs like semaglutide, while retaining their major therapeutic benefits for blood glucose control.”

The study was published in the Journal of Medicinal Chemistry.

Source: The Florey Institute