Unlocking the Dual-Target siRNA Frontier: $1B Partnership and First Clinical Approval Mark a New Era in Oligonucleotide Therapeutics

In recent years, dual-target small nucleic acid drugs have become one of the hottest fields in the global pharmaceutical industry due to their advantages such as synergistic effects and avoiding combination therapy. Despite the promising prospects of dual-target small nucleic acid drugs, their synthesis and production face multiple technical bottlenecks, which have become key obstacles in advancing pipelines.

Figure 1Schematic diagram of the structure of traditional siRNA (A) and dual-target siRNA (B)

While dual-target siRNA offers the aforementioned advantages, it also presents synthetic challenges, becoming a key obstacle hindering pipeline progress:

I.Double-Length Sense Strand。Since the sense strand of dual-target siRNA needs to complement two antisense strands, its length will reach approximately 40nt, doubling the length of the sense strand of traditional siRNA. Therefore, the number of coupling steps required for solid-phase synthesis will also increase, and the cumulative yield will significantly decrease.

2.Additional linker modificationUnlike traditional siRNA, the sense strand also requires linker modification. Taking TEG (tetraethylene glycol) linker as an example, if TEG phosphoramidite is used for synthesis, it will not only increase the number of coupling steps, but the steric hindrance it causes will further reduce the synthesis efficiency.

3.Mass ProductionCorsera Health recently announced its clinical program for a dual-target siRNA drug aimed at hyperlipidemia, marking the advancement of dual-target siRNA into the field of common metabolic diseases. This implies that dual-target siRNA will have broader user coverage and greater demand for scaled production in the future. Considering the aforementioned synthesis challenges, large-scale production of dual-target siRNA will become a significant challenge.

As a globally renowned supplier of gene monomers, Zhaowei Technology has been deeply engaged in the nucleic acid field for nearly 30 years. While continuously enhancing our existing solid-phase synthesis platform, we have also taken the lead in providing a chemo-enzymatic synthesis platform, contributing to the industrialization of dual-target siRNA.

Solid-phase synthesis platformBased on its comprehensive advantages in the nucleic acid industry chain, Zhaowei Technology can implement complete quality control from upstream raw materials (such as phosphoramidites/GalNAc/NTP) to downstream purification and formulation, thereby providing high-quality, low-cost, and stable nucleic acid products. In addition, Zhaowei Technology's solid-phase synthesis platform is equipped with the largest-scale 1800 mmol synthesis instrument currently available in the industry, with GMP scale-up capabilities reaching kilogram-level.

Figure 2Chemical-enzymatic ligation synthesis strategy for dual-target siRNA. (A) Shorter fragments obtained using solid-phase synthesis. (B) Hybridization of complementary fragments to generate enzymatic ligation sites. (C) Ligation of sites using ligase to form the complete dual-target siRNA.

Chemoenzymatic Synthesis Platform。Figure 2Showcases the latest chemo-enzymatic synthesis platform provided by Zhaowei Technology. This platform does not require the one-step synthesis of a complete long-chain sense strand; instead, it first uses solid-phase synthesis to obtain multiple short fragments (Figure 2A), thereby ensuring the synthesis quality and yield. Then, a ligase is used to ligate the fragments together to form a complete dual-target siRNA (Figure 2C). This synthetic strategy has the following characteristics:

I.Higher Yield。Due to the shortened length of solid-phase synthesis, the purity and yield of each short fragment can be guaranteed, especially for the sense strand 2 with linker modifications (Figure 2A). The reduction in coupling steps can also correspondingly lower reagent costs.

2.One-pot enzymatic ligationThe enzyme ligation reaction does not require step-by-step operations but instead converts each fragment into a complete double-stranded siRNA product through a one-pot method.

3.A Simpler Purification Solution. Typically, chromatographic purification is required after the synthesis of each short fragment (Figure 2A). Moreover, the chemo-enzymatic synthesis platform of Zhaowei Technology can adopt a purification scheme after enzymatic ligation, eliminating the purification step required after solid-phase synthesis, thereby reducing costs and improving yield.

Dual-target small nucleic acid drugs are ushering in a new era of innovative treatment. As a leader深耕 small nucleic acid CDMO 领域,Zhaowei Technology Cracks the Core Challenges of Synthesis Efficiency, Large-Scale Production, and Purity Control with a "Chemoenzymatic + Solid-Phase" Dual-Platform Technology Matrix。

In the future, Zhaowei Technology will continue to iterate its technology platform to provide more efficient and reliable CDMO services, helping global innovative pharmaceutical companies accelerate the research and development of dual-target small nucleic acid drugs.Advance the commercialization process to bring more breakthrough therapies to patients sooner!