Whenever a patient is given one dose of an antisense drug — like the spinal muscular atrophy treatment Spinraza — chances are they are actually receiving thousands of distinct versions of the compound that differ in their spatial configuration. And that can be a real problem.
Given that the 3D architecture of biological molecules often impacts their function, scientists have suggested that “stereodefined systems,” where atoms’ arrangement in space are strictly controlled, might make drugs safer and more effective.
Researchers at San Diego’s Scripps Research and Bristol-Myers Squibb think they have now come up with a solution that could benefit anyone interested in the discovery, delivery and development of gene-based medicine: a tool to potentially develop new drugs faster and refine the manufacturing of them.
With existing methods, it’s difficult to produce even a small amount of certain stereodefined isomers, let alone enough to test which particular stereoisomer out of hundreds of thousands is the most effective as a therapy or, conversely, might cause side effects.
The breakthrough here, Scripps professor Phil Baran tells me, is using a different form of phosphorus — nature’s “molecular glue” — than what’s traditionally employed to kickstart the production of oligonucleotides.
Instead of P(III), a reactive species that calls for a highly controlled setup in the synthetic process, the new reagent class created by Baran’s team and their collaborators at Bristol-Myers is based on P(V), which they say supports a quicker method to get the exact stereoisomer that one wants. Called phosphorus-sulfur incorporation or simply PSI, this method is also expected to be scalable for use in both early-stage discovery and manufacturing work.
“It’s better in almost every way,” he says.
While the application of this new tool is not tied to any modality or therapeutic area, the collaborators chose to document two specific examples in their paper, published today in Science: antisense oligonucleotides similar to Spinraza, and cyclic dinucleotides (CDNs), a class touted for its potential as a cancer immunotherapy by targeting the STING protein.
“To me the PSI reagents are a new platform of reactivity that we can leverage,” Martin Eastgate, who heads up chemical research at Bristol Myers’ chemical and synthetic development unit, tells me. “What they will enable in terms of future innovation, I think is very much to be determined.”
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