Curated reading path
Follow the real development paths of Enlicitide and ICOTYDE from screening hits and structural optimization to oral exposure and clinical translation.
11 published articles in recommended order
PCSK9 was a validated yet difficult protein–protein interaction target. mRNA display found two cyclic-peptide hit series in a vast chemical space, but a binder was only the beginning of the drug-discovery journey.
Compound 30 enabled the first co-crystal structure for this PCSK9 macrocycle series, making its binding mode visible and turning empirical SAR into testable structure-based design hypotheses.
Compound 30 had a clear PCSK9 binding mode, but stability, PK, safety, and solubility remained unresolved. Structure-guided D-amino-acid substitution, bicyclization, and N-methylation advanced the series while revealing new developability liabilities.
From the established bicyclic platform to tricyclic Compound 35 and property-engineered Compound 44, the program combined potency, stability, PK, and an enabled formulation to demonstrate oral PCSK9 target engagement in primates.
Starting from oral proof-of-concept lead Compound 1a, the team addressed oxidation, solubility, process-safety, and isomer liabilities through a five-module platform and selected Compound 18—MK-0616/Enlicitide.
The oral development of ICOTYDE first addresses not substantial systemic absorption, but gastrointestinal stability. Peptide 1185 demonstrates how cyclization, terminal capping, and engineered residues such as Pen, 2-Nal, F(4-2ae), and Lys(Ac) can jointly expand the chemical space of natural peptides.