siRNAs

What are siRNAs?

Small interfering RNAs (siRNAs) are naturally occurring or artificial, 20-25-nucleotide-long double-stranded RNA molecules that suppress gene expression via RNA interference (RNAi). This process involves siRNA binding to complementary messenger RNA (mRNA) and promoting its degradation, thereby silencing specific gene expression. This precision process renders siRNAs indispensable for both genetic analysis and drug development.

Figure 1. Mechanism of action of siRNAs^[1].

What is the mechanism of action of siRNAs?

RNAi is the main mechanism by which siRNA acts and can be roughly broken down into two phases:

Initiating Phase

• Generation of dsRNA: Long double-stranded RNA (dsRNA) or short hairpin RNA (shRNA) is cut into small double-stranded RNA (i.e. siRNA, by Dicer enzyme inside the cell. These siRNA fragments are usually 21-23 nucleotides long with two phosphorylated outward-protruding motifs at the 3' end.
• Unwinding of siRNA: siRNA double strands unwinded in RNA induced silencing complex (RISC) to create a single strand. One strand is called the guide strand and the other is called the passenger strand, which is usually degraded.

Effector Phase

• RISC assembly and activation: The guide strand attaches to the Argonaute protein in RISC to generate an active RISC complex, which recognizes and binds mRNAs wholly complementary to its guide strand.
• Cleavage and degradation of mRNA: The nucleic acid endonuclease in the RISC complex cuts the mRNA target and destroys it. This is what prevents the translation of the mRNA, which stops the expression of particular genes.

The siRNA achieves post-transcriptional silencing of the target gene by specifically binding to the target mRNA and activating the RISC complex. It's an important tool in gene regulation and disease therapy, but its delivery efficiency and stability remains to be improved.

What are siRNAs used for?

Therapeutics

The treatments for cancer, viral infections, and genetic disorders are being changed by siRNAs. As treatments, siRNAs give unmatched specificity by attacking disease-specific mRNAs. The FDA-approved therapies Patisiran for hereditary transthyretin-mediated amyloidosis and Givosiran for acute hepatic porphyria are two good examples.

Biomedical Research

We commonly use siRNAs to study the function of genes by knocking down genes briefly in vitro or in vivo. This makes it possible to research signalling pathways, pathophysiology, and drug targets.

Figure 2. Development process of siRNA therapeutics for cancer treatment^[2].

siRNA Development Services at Alfa Chemistry

Alfa Chemistry specializes in the design and synthesis of high-quality siRNAs tailored for research and therapeutic needs. Our offerings include:

• Target selection.
• Sequence design of siRNAs.
• Synthesis and chemical modification of siRNAs.
• Purification and analysis of siRNAs.
• Delivery system selection or development of siRNAs.
• Nonclinical evaluation of siRNAs.
• Scale-up of siRNAs.

siRNAs are the new revolution in gene therapy and molecular biology. As chemical modifications and delivery methods become more refined, the ability of siRNAs to solve unmet medical need also increases. Alfa Chemistry will continue to be a supporter of researchers and clinicians with the most innovative siRNA solutions, depending on the needs of each.

Our products and services are for research use only and cannot be used for any clinical purposes.

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