Phosphorus reagent constructs nucleotides

Abstract

Antisense drugs are on the rise. The U.S. FDA has approved two antisense therapies to treat genetic diseases in the past two years, with more in the pipeline. These compounds often consist of nucleoside chains connected by phosphorothioates—chiral linkages that make the agents more stable in the body yet exponentially increase their complexity. For example, the 18-mer Spinraza, which is a spinal muscular atrophy drug from Ionis and Biogen that costs $125,000 per dose, incorporates these linkages and is delivered as a mixture of up to 130,000 isomers. Controlling the stereochemistry at phosphorus, though, could increase a drug candidate’s potency by reducing the number of less-active isomers in these mixtures. To gain that control, chemists have mostly turned to phosphorus(III)-based chemistry. Now, scientists at Bristol-Myers Squibb and Scripps Research Institute California report a novel P(V)-based reagent that couples nucleosides with high diastereoselectivity (Science 2018, DOI: 10.1126/science.aau3369...