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Rational Design and Screening of Chemically Modified Anti-SARS-CoV-2 siRNA.

Zihui Cheng1,2,3, Ying Cai1,2, Enhua Zhang4

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201210, China.

ACS Infectious Diseases
|April 27, 2026
PubMed
Summary
This summary is machine-generated.

Chemical modifications enhance small interfering RNA (siRNA) stability and potency for treating severe acute respiratory syndrome coronavirus 2. Optimized siRNA VS-159m102 shows superior gene silencing and stability, offering potential for new therapeutics.

Keywords:
RdRpSARS-CoV-2asymmetric modificationmodification patternsiRNA

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • RNA interference (RNAi) holds therapeutic promise for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • Chemical modifications are essential for improving small interfering RNA (siRNA) stability and efficacy.
  • Identifying effective siRNA candidates targeting conserved viral genes is critical.

Purpose of the Study:

  • To optimize siRNA chemical modifications for enhanced SARS-CoV-2 gene silencing.
  • To identify lead siRNA compounds and systematically evaluate modification patterns.
  • To develop a potent and stable siRNA therapeutic candidate.

Main Methods:

  • Screened 200 siRNAs targeting the conserved RNA-dependent RNA polymerase gene of SARS-CoV-2.
  • Introduced 2'-fluoro (2'-F) and 2'-O-methyl (2'-OMe) substitutions on siRNA strands.
  • Incorporated asymmetric 3'-end modifications (GNA, TNA, LNA) on the sense strand.

Main Results:

  • Identified VS-38m as a lead siRNA compound.
  • Systematic evaluation of modification patterns led to optimized siRNA VS-159m102.
  • VS-159m102 demonstrated picomolar gene-silencing efficacy, reduced cytotoxicity, and improved serum stability.

Conclusions:

  • Optimal chemical modifications significantly enhance siRNA stability and potency against SARS-CoV-2.
  • The developed VS-159m102 siRNA represents a promising therapeutic candidate.
  • Findings provide valuable insights for designing future siRNA therapeutics.