The fidelity of intracellular signaling pathways requires that cells control the production of signaling agents in space and in time. Phosphatidic acid (PA) is both a central phospholipid biosynthetic intermediate and a multifunctional lipid second messenger produced at several discrete subcellular locations. The modes of action of PA can differ based on upstream stimulus, biosynthetic source, and site of production. How cells regulate the local production of PA to direct diverse signaling outcomes remains elusive.
Abstract Body: Non-adherence is a major hurdle for the effective treatment of HIV, a global epidemic even after 30 years of medical advancements. Long-acting therapeutics have the potential to improve adherence through simplified regimens. One such investigational medication is MK-8591, a nucleoside reverse transcriptase translocation inhibitor with subnanomolar antiviral activity and a long intracellular half-life. To support this program, a world-class manufacturing synthesis which is robust, green, and sustainable was targeted.
Natural sources, such as plants, fungi and microbes, have historically provided compounds with potent pharmaceutical properties. While it can be challenging to build complex natural products in a lab using existing chemistry methods, Nature has perfected these biosynthetic pathways. The work described leverages the power of Nature’s tools for building complex molecules to synthesize novel molecules with therapeutic potential. The reactivity and selectivity of enzymes from natural product pathways are often unparalleled in existing chemical methods.