"Linaclotide’s unique three-dimensional structure “gives the molecule certain thermal and metabolic stability that is unusual for a peptide,” says Angelika Fretzen, Ironwood’s vice president for pharmaceutical chemistry and development. The polypeptide consists of 14 natural amino acids, six of which are cysteines that pair to form three disulfide bridges. The result is a multicyclic knot that can resist enzymatic degradation in the gut.
For early studies, the company used its in-house expertise to make variants of the peptide recombinantly rather than through chemical synthesis, Fretzen explains. Synthesis became the pragmatic approach. “When we started to see there was something interesting that we wanted to take forward into the clinic, we approached manufacturers to get the needed amounts.”
Synthesizing a tightly bound polypeptide can be challenging, but over the past 30 years peptide synthesis and purification have matured. A turning point came in 2003 when Roche launched its HIV drug Fuzeon, a then-unheard-of 36-amino-acid-long polypeptide that Roche succeeded in making via solid-phase synthesis.
“The whole peptide manufacturing world had undergone a shift to commercial feasibility, and so it was the right way to go,” Fretzen says about choosing the synthetic route.
Today, Ironwood has commercial supply agreements with two peptide manufacturers. One is PolyPeptide Laboratories, working through its Torrance, Calif., and Malmö, Sweden, locations. The other is CordenPharma Colorado, the former Roche Colorado peptide manufacturing operation, which Roche sold to investors ICIG in 2011."
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