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Unlocking the potential of RNAi as a therapeutic strategy against infectious viruses: an in-silico study

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Abstract

RNA interference is an upcoming methodology being designed to specifically target viral infections. The current study suggests a strategy to design probable small interfering RNAs (siRNA) for targeting the viral genome of SARS-CoV-2, as a case study. siRNAs were designed against the targets from a highly conserved region of the spike gene of SARS-CoV-2 having no significant matches within the human genome. Four targets/viral RNAs (vRNA) with high predicted inhibition values were selected for further evaluation. The predicted siRNAs were examined for their properties and stability using molecular dynamics (MD) simulations. Further, to understand the RNA-Induced Silencing Complex (RISC) mechanism of the predicted siRNA targets of SARS-CoV-2, the human argonaute (Ago2) protein in complex with the four siRNA-vRNA duplexes was built. MD simulations of apo-Ago2, four selected siRNA-vRNA duplexes and four Ago2 bound to these siRNA-vRNA duplexes were carried out for 1 μs each. Amongst the four duplex-bound Ago2 simulation systems, the siRNA-vRNA3 duplex showed stable base pairing in the seed region, favourable and strong interactions with functionally important residues of Ago2 protein through the simulation length. Therefore, the designed siRNA3 molecule may act as an effective therapeutic agent against the SARS-CoV-2. The reported in-silico strategy may be beneficial for the identification and designing of probable siRNAs against any viral genome in RNAi therapeutics. However, the experimental validation of these molecules would be required for proving their use as therapeutics.

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Acknowledgements

The authors acknowledge the Bioinformatics Resources and Applications Facility (BRAF), of C-DAC, for providing a supercomputing facility to carry out molecular dynamics simulations. The authors also acknowledge National Supercomputing Mission (NSM), India & Ministry of Electronics and Information Technology (MeitY), and Department of Science and Technology (DST) for the support to perform R&D work at C-DAC.

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  1. Mallikarjunachari V. N. Uppuladinne, Shruti Koulgi, Vinod Jani have contributed equally co-first authorship.

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  1. High Performance Computing - Medical and Bioinformatics Applications, Centre for Development of Advanced Computing (C-DAC), Panchavati, Pashan, Pune, Maharashtra, 411008, India

    Mallikarjunachari V. N. Uppuladinne, Shruti Koulgi, Vinod Jani, Uddhavesh Sonavane & Rajendra Joshi

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  1. Mallikarjunachari V. N. Uppuladinne
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  2. Shruti Koulgi
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Uppuladinne, M.V.N., Koulgi, S., Jani, V. et al. Unlocking the potential of RNAi as a therapeutic strategy against infectious viruses: an in-silico study. Chem. Pap. 78, 1537–1552 (2024). https://doi.org/10.1007/s11696-023-03180-w

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