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Presenter highlights diastereomer and stereochemistry challenges for oligonucleotide generics
Summary
The presenter explained how non-stereospecific phosphorothioate and other linkages create chiral centers, producing 2^m diastereomers that can range from thousands to more than a billion in antisense oligonucleotides, complicating sameness comparisons.
The presenter explained that non-stereospecific phosphorothioate (PS) modifications introduce new chiral centers, producing mixtures of R and S configurations that multiply with each modified linkage. "If the PS modification, is non stereo specific, it would introduce a chiral center, a new chiral center, with a mixture of r and s configurations as a certain ratios," he said, noting that multiple PS sites can yield 2^m diastereomers.
He contrasted siRNA products, which often have relatively small numbers of possible diastereomers, with antisense oligonucleotides (ASOs) where the number of diastereomers can range from thousands to millions to more than one billion. The presenter used slide data to show concrete strand-level counts and said that this combinatorial explosion increases analytical and sameness-assessment difficulty for generics.
