How recoded E. coli could lower the cost of making weight-loss drugs

Constructive Bio's recoded E. coli can build long peptides containing non-canonical amino acids by fermentation, opening a route to making GLP-1 weight-loss drugs at lower cost and with less toxic waste than chemical synthesis.

The peptides behind many weight-loss drugs are difficult and expensive to make at scale. A recoded strain of Escherichia coli could change that, lowering the cost of production and cutting the waste that current methods generate.

The strain, engineered to build proteins using 61 codons rather than the usual 64, is now being applied as a manufacturing route for peptides that carry non-natural chemistries. Constructive Bio built the recoded strain and is developing it to produce high-volume peptide and protein therapies that have been hard to manufacture by conventional means.

"Our key message is that we're able to produce long peptides containing non-canonical amino acids to deliver therapeutic proteins at scale by biomanufacturing," says Rob Salmon, PhD, head of bioprocess at Constructive Bio. "And our key differentiator is there's currently a market in, for example, weight loss drugs."

Glucagon-like peptide-1 (GLP-1) agonists, the active ingredients in several weight-loss treatments, are usually made by chemical routes such as solid phase peptide synthesis. Salmon points out that those methods are hard to scale and produce large volumes of toxic waste. The recoded strain offers an alternative: making the same peptides by fermentation, using the kind of standardised processes that industrial biomanufacturing already relies on.

"We want to fit into standardised industrial unit operations and, through that, scale to thousands of litres of product that we can sell to the market," he says.

The strain came out of work to reduce the number of codons an organism needs to build proteins, from 64 down to 61. Freeing up those three codons creates slots for three new non-canonical amino acids, which the ribosome can then incorporate into a growing peptide chain.

Constructive Bio was founded in 2022 to take the strain into industrial use, including optimising it for products such as antibody fragments and the long peptides used in GLP-1 therapies. The optimised strain has since been run through industrial fermentations and reached promising titres. Salmon will present those results at the upcoming Bioprocessing Summit in Boston.

"We're challenging some of the assumptions from chemists that biology can't be used to do this," he says.