Simon Fraser University Chemists Speed Up Nucleoside Analogue Production
Researchers at Simon Fraser University developed a modular chemical method that turns cheap starting materials into potential antiviral drug candidates in weeks instead of months or years. The technique, published in the journal Science, addresses a long-standing manufacturing bottleneck that makes complex nucleoside analogues notoriously difficult and inefficient to build for pharmaceutical screening.
Nucleoside analogues serve as molecular lookalikes that trick cells or infecting viruses into using fake building blocks rather than natural DNA and RNA components. This disruption stops viruses from reproducing, a mechanism utilized by more than 30 approved medications, including the COVID-19 treatment remdesivir and therapies for HIV and hepatitis.
Traditionally, producing these molecules requires a fixed, linear sequence of 15 or more chemical reactions starting from a naturally occurring sugar molecule. Early manufacturing of remdesivir yielded less than two percent usable drug from its starting material, and assembling a library of roughly 1,000 candidate molecules took a major pharmaceutical company many years.
The Britton Lab Modular Synthesis Platform
The research team at The Britton Lab used an amino acid catalyst to build a versatile core intermediate containing a chemical connector that can be stored in large batches. Instead of building every target molecule separately from scratch, the laboratory used a visible-light-driven reaction in a final step to join this core piece to many different molecular fragments.
This approach allowed the researchers to generate a library of more than 70 nucleoside analogues in parallel. The library includes modified sugar rings containing sulfur or nitrogen atoms, along with versions designed to penetrate cell membranes more easily.
One previously studied molecule that originally required 16 synthetic steps was produced using the new platform in just six steps. Collaborator Ralph Pantophlet’s laboratory at Simon Fraser University tested the compounds in a cell-based assay against HIV and identified three candidates that block the virus as effectively as some currently approved medications.
New platform accelerates early stage drug research
The platform allows laboratories to generate collections of drug candidates 10 to 100 times larger than previously practical within weeks. While identifying these starting points more quickly accelerates early-stage research, the newly identified compounds face a long path ahead before reaching clinical trials.
What are nucleoside analogues and how is production faster?
What is a nucleoside analogue?
Nucleoside analogues are lab-made molecular lookalikes of DNA and RNA building blocks that disrupt viral reproduction by tricking viruses into using them instead of natural nucleosides. More than 30 approved medicines operate through this mechanism.
How did the new method reduce production time?
The Britton Lab bypassed traditional multi-step linear synthesis by creating a versatile core intermediate using an amino acid catalyst, then joining it to various molecular fragments in a single visible-light-driven step. This allowed researchers to build over 70 analogues in parallel within weeks.
Which viruses were tested using the newly synthesized compounds?
Ralph Pantophlet’s laboratory at Simon Fraser University tested the generated compounds against HIV in a cell-based assay, identifying three candidate molecules that matched the virus-blocking effectiveness of certain approved medications.
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