Chris Nawrat, Merck Process
Faculty host: Prof. Dudley
Department of Process Research and Development
Merck & Co., Inc
With 37 million people around the world infected with HIV—and this number rising by almost 2 million a year—the search for newer, better medicines to treat this disease remains an important goal. MK-8591 is a nucleoside reverse transcriptase inhibitor currently undergoing clinical trials for the treatment of HIV.
In order to achieve a world-class manufacturing route to this target that is also green and sustainable, the process chemistry team has turned to biocatalysis. Specifically, the 4’-ethynyl-2’-deoxyribose sugar portion of the molecule is prepared via a highly efficient three-enzyme cascade sequence. Another multi-enzyme reaction system is then used to append the 2-fluoroadenine base, providing an unusual solution to a challenging glycosylation reaction.
This bold endeavor has posed numerous technical challenges in the optimization of complex multi-enzyme systems, the need for directed evolution of multiple enzymes, the detection and analysis of polar chromophore-free molecules and the isolation of unstable and highly water-soluble intermediates. An overview of the ongoing development and unique challenges—and opportunities—of this unprecedented fully-enzymatic manufacturing route will be presented.