10SB

PCSK9 in complex with cyclic peptide 21

This is a non-PDB format compatible entry.

Summary for 10SB

• Entry DOI: 10.2210/pdb10sb/pdb
• Descriptor: Propeptide of Proprotein convertase subtilisin/kexin type 9, Proprotein convertase subtilisin/kexin type 9, Cyclic peptide 21, ... (7 entities in total)
• Functional Keywords: cholesterol, ldl receptor, egfa domain, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 48173.13

Authors

Orth, P.,Hong, M.R.,Klein, D.J. (deposition date: 2026-02-04, release date: 2026-06-03)

Primary citation

Josien, H.,Nair, A.G.,Ding, F.X.,Guo, Y.,Chen, Y.H.,Rao, A.U.,Liu, J.,Tong, L.,Sun, Z.,Lo, M.M.,Tucker, T.J.,Embrey, M.W.,Shahripour, A.,Wu, C.,Bianchi, E.,Branca, D.,Kuethe, J.T.,Lee, J.,Thaisrivongs, D.A.,Bulger, P.G.,Zhu, X.,Ha, S.N.,Johnston, J.M.,Klein, D.J.,Orth, P.,Hong, M.R.,Buevich, A.V.,Gao, Q.,Zokian, H.J.,Koeplinger, K.A.,Tracy, R.W.,Hafey, M.J.,Buist, N.,Bueters, T.,Alleyne, C.,Bass, A.,Campeau, L.C.,Johns, D.G.,Garbaccio, R.M.,Vachal, P.,Walji, A.,Wood, H.B.
Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR.
J.Med.Chem., 2026

PubMed Abstract: Herein, we report the discovery process of enlicitide (MK-0616, compound ), an orally active macrocyclic peptide therapeutic against PCSK9 for LDL-C reduction. To overcome development bottlenecks in a prior lead (compound ) in a timely manner (sulfur oxidation liability, low solubility, azido potential manufacturing hazard, and alkene isomeric complexity), we deployed a novel scalable solution-phase modular fragment assembly (North/East/South/West/tail), which allowed us to accelerate the design-make-test-analyze (DMTA) cycle and preclinical profiling. Design solutions were quickly validated through this approach (a northern lactam staple, an -benzylamide southern spacer, an RCM-derived cross-link in conjunction with solvent-exposed motifs to modulate solubility) and delivered compounds with low picomolar potency, improved solubility, stability, and PK from which enlicitide (MK-0616, compound ) was selected for clinical progression. This modular strategy may act as a template to accelerate late-stage issue-driven SAR in highly engineered macrocyclic peptides.

PubMed: 42201324
DOI: 10.1021/acs.jmedchem.6c00463

Experimental method

X-RAY DIFFRACTION (1.828 Å)