High resistance barrier and prophylactic protection in preclinical models of SARS-CoV-2 with two siRNA combination.

ABSTRACT: RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral RNA. We identified potent lipophilic small interfering RNA (siRNA) conjugates targeting highly conserved regions of SARS-CoV-2 outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single siRNA approach. Viral resistance to single siRNA treatment occurred due to emergence of point mutations at critical positions required for siRNA-mediated target binding and cleavage, which led to a loss of siRNA efficacy. With a two-siRNA combination, emergence of mutations within the siRNA binding site was abolished. When

SUBMITTER: Anglero-Rodriguez YI 

PROVIDER: S-EPMC11724309 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature