Improving the Gastrointestinal Stability of Linaclotide

High susceptibility
to proteolytic degradation in the gastrointestinal
tract limits the therapeutic application of peptide drugs in gastrointestinal
disorders. Linaclotide is an orally administered peptide drug for
the treatment of irritable bowel syndrome with constipation (IBS-C)
and abdominal pain. Linaclotide is however degraded in the intestinal
environment within 1 h, and improvements in gastrointestinal stability
might enhance its therapeutic application. We therefore designed and
synthesized a series of linaclotide analogues employing a variety
of strategic modifications and evaluated their gastrointestinal stability
and pharmacological activity at its target receptor guanylate cyclase-C.
All analogues had substantial improvements in gastrointestinal half-lives
(>8 h vs linaclotide 48 min), and most remained active at low nanomolar
concentrations. This work highlights strategic approaches for the
development of gut-stable peptides toward the next generation of orally
administered peptide drugs for the treatment of gastrointestinal disorders.