Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR - PubMed
2 hours ago
- #macrocyclic peptide
- #PCSK9 inhibitor
- #fragment-based drug discovery
- The paper details the discovery process of enlicitide (MK-0616), an orally active macrocyclic peptide targeting PCSK9 for LDL-C reduction.
- To address issues in a prior lead compound (1a) like sulfur oxidation, low solubility, and manufacturing hazards, a novel fragment-based synthetic assembly approach was used.
- A modular solution-phase assembly (North/East/South/West/tail) accelerated the design-make-test-analyze cycle, enabling rapid validation of design solutions.
- Key improvements included a northern lactam staple, an N-benzylamide southern spacer, and an RCM-derived cross-link, enhancing solubility and stability.
- The approach yielded compounds with low picomolar potency and improved pharmacokinetics, leading to the selection of enlicitide for clinical development.
- This modular strategy is proposed as a template for accelerating issue-driven SAR in engineered macrocyclic peptides.