Abstract:

Atherosclerotic cardiovascular disease remains the leading cause of death worldwide, and inhibition of PCSK9 has emerged as an effective strategy for lowering LDL cholesterol and reducing cardiovascular risk. Enlicitide is a recently approved oral macrocyclic peptide designed to inhibit PCSK9, with the potential to combine the potency and specificity of biologic therapies with the convenience of a tablet.

The development of enlicitide presented an extraordinary manufacturing challenge. Early synthetic routes contained more than seventy steps, relied heavily on protecting-group manipulations, and required extensive chromatographic purification, making commercial production impractical. To address these limitations, Merck scientists reimagined the synthesis through a highly convergent process that integrates synthetic chemistry, protein engineering, and biocatalysis.

This lecture will describe how engineered enzymes, developed through directed evolution, enabled selective peptide coupling, fragment assembly, and macrocyclization reactions that were difficult or impossible to achieve efficiently using traditional chemistry. The resulting process employs biocatalytic cascades, cofactor recycling systems, protecting-group-free transformations, and crystallization-based purification, dramatically simplifying synthesis while enabling large-scale manufacture. Together, these innovations transformed a complex laboratory route into a commercially viable process and provide a blueprint for the future production of macrocyclic peptide therapeutics.

Bio:

Donald R. Gauthier, Jr., Ph.D. is a Senior Principal Scientist in Small Molecule Process Research & Development at Merck & Co., Inc. and a 30-year veteran of Merck, where he has led the development of innovative manufacturing processes for numerous clinical and commercial medicines. Dr. Gauthier earned his B.S. in Chemistry from the UMass Dartmouth and his Ph.D. in organic chemistry from the University of California, Irvine, where he conducted doctoral research under Professor Ken Shea, followed by postdoctoral studies with Professor Erick Carreira at Caltech.

Dr. Gauthier currently leads process development activities for enlicitide (MK-0616), an FDA approved oral macrocyclic peptide PCSK9 inhibitor. His work focuses on applying biocatalysis, protein engineering, and innovative process chemistry to enable the large-scale manufacture of complex medicines.