In a recent survey, three-in-four respondents said they would prefer a once‑daily oral pill over a weekly injection of GLP-1s. So why aren't there more oral options?
What fascinates me here is the engineering mindset behind GLP-1 drugs. The biology was known decades ago, but the real breakthrough came from chemical tweaks that stretched a molecule’s lifetime from minutes to days. Sometimes innovation is less about discovery and more about persistence in optimisation.
>one must gain FDA approval by clinically demonstrating that the delivery of the microbe-encapsulated GLP-1 through this oral route leaves the drug molecule itself unchanged (with no post-translational modifications)
On the topic of post-translational modifications: how would the cyanobacteria be expected to put in the Aib and attach the lipid to the lysine? (The Aib might be particularly hard)
From the author, David Kim: Great question, short answer is that you will struggle to make semaglutide per se. But other GLP-1 drugs like lixisenatide or exenatide could be made.
Long answer:
So far, GLP-1 drugs that do not have non-canonical amino acids are far easier to turn into oral GLP-1 drugs. For example, exenatide (AstraZeneca) and lixisenatide (Sanofi) have only canonical amino acids and no lipidations. Therefore, as long as one can adequately demonstrate to the FDA that there are no new post-translational modification (PTMs) introduced by the expression host, the whole cell-encapsulated oral formulation of a GLP-1 peptide could be approved via the 505(b)2 pathway. This is conditional on having satisfactory safety, toxicology and PK/PD, but is only a viable approval route if the peptide is less than 41 amino acids in length under the current guidance.
To make semaglutide, quite right to point out that one has to incorporate non-canonical amino acids which currently, these cells cannot perform. But it is possible. This can be done through engineering orthogonal aminoacyl–tRNA synthetase (aaRS)/tRNA pairs to assign a new non-canonical amino acid, such as Aib, to an orthogonal codon (often by repurposing the UAG stop codon). 'Genetic code expansion' has been demonstrated in E coli by several groups using different approaches (Dunkelmann et al 2021, Costello et al 2024). Since it is a relatively recent field, so far, no one has published that they've replicated this in cyanobacteria, algae or any other edible organism — even though this could be a major missed opportunity if successful.
As for lipidations, it is harder to engineer specificity. Interestingly, cyanobacteria natively express enzymes called prenyltransferases. Prenylation, though only a subset of lipidation, can attach isoprenoid lipids (C15, C20) to a peptide's cysteine residues. This would not enable us to make semaglutide, but it opens doors to other peptide designs with lipid tails that can bind to albumin.
Great question, short answer is that you will struggle to make semaglutide per se. But other GLP-1 drugs like lixisenatide or exenatide could be made.
Long answer: So far, GLP-1 drugs that do not have non-canonical amino acids are far easier to turn into oral GLP-1 drugs. For example, exenatide and lixisenatide have only canonical amino acids and no lipidations. Therefore, as long as one can adequately demonstrate that there are no new post-translational modification (PTMs) introduced by the expression host, the whole cell-encapsulated oral formulation of a GLP-1 peptide could be approved, conditional on having shown satisfactory safety, toxicology and PK/PD clinically.
To make semaglutide, quite right to point out that one has to incorporate non-canonical amino acids which currently, these cells cannot perform. But it is possible. This can be done through engineering orthogonal aminoacyl–tRNA synthetase (aaRS)/tRNA pairs to assign a new non-canonical amino acid, such as Aib, to an orthogonal codon (often by repurposing the UAG stop codon). 'Genetic code expansion' has been demonstrated in E coli by several groups using different approaches (Dunkelmann et al 2021, Costello et al 2024). Since it is a relatively recent field, so far, no one has published that they've replicated this in cyanobacteria, algae or any other edible organism — even though this could be quite an interesting avenue to pursue.
Imho, the real hard question is the inconsistency of bioavailability of the oral GLP1a form (in currently existing formulations) not only on an individual basis but also with each administration. Basically, the oral form currently, it seems, delivers a "whatever" actual dosage. Thus, the potential long-term consequences of such inconsistency are in question, which might range from the broad swing of the "ordinary" side effects to the serious stuff that is more prevalent, it seems, with abrupt start/stops instead of gradual tapering of injected dosages.
What fascinates me here is the engineering mindset behind GLP-1 drugs. The biology was known decades ago, but the real breakthrough came from chemical tweaks that stretched a molecule’s lifetime from minutes to days. Sometimes innovation is less about discovery and more about persistence in optimisation.
>one must gain FDA approval by clinically demonstrating that the delivery of the microbe-encapsulated GLP-1 through this oral route leaves the drug molecule itself unchanged (with no post-translational modifications)
On the topic of post-translational modifications: how would the cyanobacteria be expected to put in the Aib and attach the lipid to the lysine? (The Aib might be particularly hard)
From the author, David Kim: Great question, short answer is that you will struggle to make semaglutide per se. But other GLP-1 drugs like lixisenatide or exenatide could be made.
Long answer:
So far, GLP-1 drugs that do not have non-canonical amino acids are far easier to turn into oral GLP-1 drugs. For example, exenatide (AstraZeneca) and lixisenatide (Sanofi) have only canonical amino acids and no lipidations. Therefore, as long as one can adequately demonstrate to the FDA that there are no new post-translational modification (PTMs) introduced by the expression host, the whole cell-encapsulated oral formulation of a GLP-1 peptide could be approved via the 505(b)2 pathway. This is conditional on having satisfactory safety, toxicology and PK/PD, but is only a viable approval route if the peptide is less than 41 amino acids in length under the current guidance.
To make semaglutide, quite right to point out that one has to incorporate non-canonical amino acids which currently, these cells cannot perform. But it is possible. This can be done through engineering orthogonal aminoacyl–tRNA synthetase (aaRS)/tRNA pairs to assign a new non-canonical amino acid, such as Aib, to an orthogonal codon (often by repurposing the UAG stop codon). 'Genetic code expansion' has been demonstrated in E coli by several groups using different approaches (Dunkelmann et al 2021, Costello et al 2024). Since it is a relatively recent field, so far, no one has published that they've replicated this in cyanobacteria, algae or any other edible organism — even though this could be a major missed opportunity if successful.
As for lipidations, it is harder to engineer specificity. Interestingly, cyanobacteria natively express enzymes called prenyltransferases. Prenylation, though only a subset of lipidation, can attach isoprenoid lipids (C15, C20) to a peptide's cysteine residues. This would not enable us to make semaglutide, but it opens doors to other peptide designs with lipid tails that can bind to albumin.
Great question, short answer is that you will struggle to make semaglutide per se. But other GLP-1 drugs like lixisenatide or exenatide could be made.
Long answer: So far, GLP-1 drugs that do not have non-canonical amino acids are far easier to turn into oral GLP-1 drugs. For example, exenatide and lixisenatide have only canonical amino acids and no lipidations. Therefore, as long as one can adequately demonstrate that there are no new post-translational modification (PTMs) introduced by the expression host, the whole cell-encapsulated oral formulation of a GLP-1 peptide could be approved, conditional on having shown satisfactory safety, toxicology and PK/PD clinically.
To make semaglutide, quite right to point out that one has to incorporate non-canonical amino acids which currently, these cells cannot perform. But it is possible. This can be done through engineering orthogonal aminoacyl–tRNA synthetase (aaRS)/tRNA pairs to assign a new non-canonical amino acid, such as Aib, to an orthogonal codon (often by repurposing the UAG stop codon). 'Genetic code expansion' has been demonstrated in E coli by several groups using different approaches (Dunkelmann et al 2021, Costello et al 2024). Since it is a relatively recent field, so far, no one has published that they've replicated this in cyanobacteria, algae or any other edible organism — even though this could be quite an interesting avenue to pursue.
This is a very well written and accessible explanation for what otherwise seems to be a very complex topic.
Imho, the real hard question is the inconsistency of bioavailability of the oral GLP1a form (in currently existing formulations) not only on an individual basis but also with each administration. Basically, the oral form currently, it seems, delivers a "whatever" actual dosage. Thus, the potential long-term consequences of such inconsistency are in question, which might range from the broad swing of the "ordinary" side effects to the serious stuff that is more prevalent, it seems, with abrupt start/stops instead of gradual tapering of injected dosages.