Controlling Phosphorothioate Stereochemistry: Challenges and Innovations in Oligonucleotide Manufacturing

Overview

Phosphorothioate (PS) linkages are foundational to the stability and efficacy of many RNA therapeutics—but controlling their stereochemistry remains one of the most persistent challenges in oligonucleotide manufacturing. As programs scale, diastereomeric complexity can limit yield, increase variability, and complicate analytical characterization.

In this session, featured at TIDES USA 2026, we explore how advanced enzymatic approaches are enabling a new level of control over PS stereochemistry—without compromising scalability.

Abstract

Phosphorothioate diester linkages play a critical role in the efficacy of many RNA therapeutics. However, these linkages introduce inherent diastereomeric complexity, creating challenges for both manufacturing and analytical characterization. This presentation highlights how Codexis’ ECO Synthesis® Manufacturing Platform enables control over diastereomeric composition, facilitating the scalable production of high‑quality siRNA.

Key Takeaways

• Why phosphorothioate stereochemistry matters for efficacy, consistency, and manufacturability
• The practical limitations of conventional approaches to PS control
• How enzymatic synthesis enables control over diastereomeric composition at scale
• Implications for siRNA quality, reproducibility, and downstream processing

Who Should Watch

Process chemists, CMC leaders, and manufacturing teams working on oligonucleotide and RNA therapeutic development