**5. Conclusion**

Small interfering RNAs are not optimal to be used as therapeutics *in vivo*, therefore, development of the approached aimed to improve or/and optimize the properties of siРНК is of significance nowadays. One of the approaches widely used is chemical modification of siRNAs. At the beginning this approach was proposed as a way to increase nuclease resistance of siRNA in the presence of serum, in the cells and bloodstream [61, 62]. The enhancement of nuclease resistance of siRNA by chemical modification not resulting in the drop of its silencing activity represent a complex task, since silencing activity of siRNA is strongly affected by the nature, number and locations within the duplex of chemical modifications [65, 76, 181]. Despite many works carried out in this area, a general algorithm which allows receiving active nuclease resistant siRNA is not developed yet.

Structure - Functions Relations in Small Interfering RNAs 217

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Chemical modification of siRNA can be also used to develop delivery vehicles for siRNA. It is well known that naked or free siRNA is not able to penetrate through cellular membrane and accumulate in the cells. In the case of in vivo conditions, the small size of siRNA molecule promotes its rapid clearance [57]. In other words, the systems for in vivo delivery of siRNAs should provide for efficiency of cellular accumulation, specificity of delivery (if applicable), duration of silencing as well as safety and possibility of systemic administration. Today no one delivery approach encounters these criteria.

On the other hand, the low efficiency of RNAi can be a result of its unfavorable sequence determining thermodynamic properties and/or by stable secondary structure at the target site within mRNA [37, 38, 51, 52, 54]. There are several algorithms to select siRNAs of highperformance [182, 183, 184, 185, 186], however it is impossible to predict precisely silencing activity of any particular siRNA in vivo. In addition, the design of siRNA targeting chimeric or mutant genes represent of complex task since the limitations of target site selection does not allow to use these algorithms for choosing the sequence siRNA. This is why structure modifications of siRNA improving their thermodynamic properties are of interest. The forklike siRNA [158, 159], able to silence target gene more efficiently that conventional siRNA is a promising approach for creating high-performance siRNA targeted any sequence of the gene. Despite this, the number of works in this field is negligible so further research of properties of siRNA with modified structure are relevant.

To obtain high-performance siRNA often optimization of multiple parameters is required, so using modification of the siRNA structure together with its chemical modification is a promising approach. Thus, advanced research of chemically and/or structurally modified siRNA, as well as development and optimization of the algorithms for modification are important.
