Explorations of siRNA therapeutics using molecular dynamics simulations: structural impacts of 2'-ribose modifications on RNA duplex and interactions with human Argonaute-2
No Thumbnail Available
Date
2025
Authors
Tajudeen, Ridwan O.
University of Lethbridge. Faculty of Arts and Sciences
Journal Title
Journal ISSN
Volume Title
Publisher
Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
Abstract
RNA interference (RNAi) is a natural mechanism by which short strands of RNA, such as small interfering RNA (siRNA), directly control the activities of genes through targeted gene suppression. RNAi can theoretically degrade any disease-related gene in a sequence-specific manner, thereby preventing disease. As a result, siRNA is a promising therapeutic. Indeed, drugs based on siRNA have emerged to treat various diseases, including cancer, viral infections, and genetic disorders. Despite their potential, siRNA-based therapeutics pose developmental challenges due to several inherent properties such as easy degradation in vivo and unwanted off-target effects, which reduce their potency. The introduction of chemical modifications into nucleotides has been employed to improve the drug-like properties of siRNA, with five such drugs having been approved by the United States Food and Drug Administration (FDA). These drugs are used to treat diseases such as hereditary transthyretin mediated amyloidosis, acute hepatic porphyria, and primary hyperoxaluria type 1, and hypercholestomia. However, to rationally design improved drugs, we must know how existing versions work. Although an important step in this process is understanding the chemical structure of the drugs and other chemically-modified siRNA duplexes, this information is currently limited, primarily due to the extensive time requirements associated with experimental procedures. To bridge the gap in our understanding of useful siRNA modifications and thereby accelerate the transition from discovery and development to clinical trials, this research uses long-timescale molecular dynamics (MD) simulations to analyze the structural preferences of the 5 siRNA drugs approved by the FDA, namely Patisiran, Givosiran, Lumasiran, Inclisiran, and Vutrisiran, and to examine how diverse chemical modification patterns influence the overall siRNA structure and interactions with human argonaute-2, the protein that facilitates gene suppression. My findings provide valuable insight into the changes in the structural dynamics, and interactions induced by chemical modifications, offering valuable information to assist the development of new siRNA drug with enhanced therapeutic efficacies.
Description
Keywords
siRNA therapeutics , targeted gene suppression , siRNA duplexes , siRNA modifications , molecular dynamics simulations