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siRNA Backbone Modification

Small interfering RNA (siRNA) therapeutics have revolutionized precision medicine by silencing disease-causing genes. At Protheragen BioNucleics, we specialize in optimizing siRNA efficacy through advanced backbone modification strategies. As a leader in Oligonucleotide Drugs CRO and Oligonucleotide Modification Service, our siRNA Modification Service integrate cutting-edge chemistry to enhance stability, specificity, and delivery of siRNA candidates.

Overview of siRNA Backbone Modification

siRNA backbone modification involves altering the phosphate-sugar backbone to improve pharmacokinetic and pharmacodynamic properties. Unlike nucleobase or sugar modifications, backbone engineering directly impacts nuclease resistance, binding affinity, and off-target effects. Common strategies include substituting non-bridging oxygen atoms with sulfur (phosphorothioate linkages) or introducing non-natural groups to stabilize the siRNA structure. These modifications address key challenges such as rapid degradation in serum and immune activation, enabling robust in vivo performance.

Our siRNA Backbone Modification Services

Protheragen BioNucleics offers end-to-end solutions for siRNA backbone engineering, combining proprietary technologies with decades of expertise.

Phosphorothioate (PS) Linkage Integration

We strategically replace oxygen with sulfur in phosphate groups to enhance nuclease resistance while maintaining RNA-induced silencing complex (RISC) compatibility. Our platform optimizes PS placement to balance stability and minimize toxicity, a critical factor for systemic delivery.

Non-Bridging Substitutions

Beyond sulfur, we incorporate boranophosphate, methylphosphonate, or selenophosphate groups. These substitutions fine-tune siRNA duplex rigidity and interaction with serum proteins, improving biodistribution. Our team uses molecular dynamics simulations to predict substitution impacts on target binding.

Bridging Modifications

We engineer bridged nucleic acids (BNA) like locked nucleic acid (LNA) or constrained ethyl (cEt) into the backbone. These modifications increase melting temperatures of siRNA duplexes, ensuring precise strand selection during RISC loading and reducing off-target gene silencing.

Sugar-Phosphate Backbone Conjugation

To enhance delivery, we conjugate siRNAs with lipids, peptides, or polymers at backbone sites. Our proprietary linker chemistry ensures payload release in target tissues while maintaining siRNA integrity during circulation.

Stereocontrolled Synthesis

Chirality at phosphorous centers influences siRNA activity. We employ stereospecific synthesis to produce backbone-modified siRNAs with defined configurations, maximizing gene-silencing potency and reproducibility.

Analytical & Validation Support

Our services include HPLC/MS characterization, in vitro nuclease stability assays, and cell-based efficacy screens. We also validate pharmacokinetic profiles using rodent models, ensuring candidates meet preclinical development benchmarks.

Frequently Asked Questions

Q1: How do backbone modifications improve siRNA therapeutic efficacy?

Backbone modifications enhance serum stability, prolong half-life, and reduce immune recognition. By preventing enzymatic degradation, they ensure sufficient siRNA reaches target tissues, improving gene-silencing durability.

Q2: What are the challenges in designing backbone-modified siRNAs?

Over-modification can impair RISC loading or cause toxicity. Our iterative design process balances chemical alterations with functional integrity, using in silico modeling and empirical data to optimize modifications.

Q3: Can backbone modifications reduce off-target effects?

Yes. For example, phosphorothioate linkages mitigate immune activation, while stereopure synthesis minimizes unintended interactions with non-target RNAs.

Applications of siRNA Backbone Modification

Oncology: Stabilize siRNAs targeting oncogenes in tumor microenvironments.
Rare Diseases: Enhance delivery to hard-to-reach tissues (e.g., CNS, muscle).
Antiviral Therapies: Improve resistance to nucleases in viral-infected cells.
Metabolic Disorders: Prolong siRNA activity for sustained gene silencing.

Why Choose Us?

Proprietary Modification Platforms: Proprietary chemistries for backbone engineering.
End-to-End Expertise: From design to preclinical validation.
Custom Solutions: Tailored modifications for specific delivery systems (e.g., LNPs, GalNAc).

Our services and products are exclusively for authorized organizations in research, development, or manufacturing and are not intended for direct use by individuals or patients or as medical advice, diagnosis, or treatment.