Researchers at Scripps Research and Bristol-Myers Squibb are touting phosphorus-sulfur incorporation as a scalable method for the production of antisense therapies.
Antisense drugs operate by binding to specific portions of genetic information - typically RNA. As such, their efficacy and safety are derived from their three-dimensional structures. Even slight variations, which often occur when these drug substances are produced using current synthetic methods, can be problematic.
Researchers at San Diego’s Scripps Research and Bristol-Myers Squibb recently developed a new method that allows for the highly controlled, stereoselective synthesis of oligonucleotides and similar compounds that can serve as active pharmaceutical ingredients.
Phosphorus-sulfur incorporation (PSI) uses P(V) compounds rather than the traditional P(III) compounds. According to Scripps researcher Phil Baran, replacing highly reactive P(III) with P(V) reagents allows for greater stereocontrol and a quicker route to the desired products. It also has the advantage of being useful at the discovery phase and scalable for commercial manufacturing.
To demonstrate its applicability, the researchers used PSI to synthesize antisense oligonucleotides similar to Spinraza (nusinersen), a treatment for spinal muscular atrophy, and cyclic dinucleotides (CDNs), a new class of cancer immunotherapy agents.