Mitigating off-target effects of small RNAs: conventional approaches, network theory and artificial intelligence.

Autor: Bereczki Z; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary., Benczik B; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Pharmahungary Group, Szeged, Hungary., Balogh OM; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary., Marton S; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary., Puhl E; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary., Pétervári M; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Sanovigado Kft, Budapest, Hungary., Váczy-Földi M; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary., Papp ZT; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary., Makkos A; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Pharmahungary Group, Szeged, Hungary., Glass K; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Locquet F; Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany., Euler G; Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany., Schulz R; Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany., Ferdinandy P; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Pharmahungary Group, Szeged, Hungary., Ágg B; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Pharmahungary Group, Szeged, Hungary.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1111/bph.17302
Abstrakt: Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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