Explorations of siRNA therapeutics using molecular dynamics simulations: structural impacts of 2'-ribose modifications on RNA duplex and interactions with human Argonaute-2

Tajudeen, Ridwan O.; University of Lethbridge. Faculty of Arts and Sciences

Explorations of siRNA therapeutics using molecular dynamics simulations: structural impacts of 2'-ribose modifications on RNA duplex and interactions with human Argonaute-2

dc.contributor.author	Tajudeen, Ridwan O.
dc.contributor.author	University of Lethbridge. Faculty of Arts and Sciences
dc.contributor.supervisor	Wetmore, Stacey D.
dc.date.accessioned	2025-09-15T17:54:12Z
dc.date.available	2025-09-15T17:54:12Z
dc.date.issued	2025
dc.degree.level	Masters
dc.description.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.
dc.embargo	No
dc.identifier.uri	https://hdl.handle.net/10133/7130
dc.language.iso	en_US
dc.publisher	Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
dc.publisher.department	Department of Chemistry and Biochemistry
dc.publisher.faculty	Arts and Science
dc.relation.ispartofseries	Thesis (University of Lethbridge. Faculty of Arts and Science)
dc.subject	siRNA therapeutics
dc.subject	targeted gene suppression
dc.subject	siRNA duplexes
dc.subject	siRNA modifications
dc.subject	molecular dynamics simulations
dc.subject.lcsh	Dissertations, Academic
dc.subject.lcsh	Molecular dynamics
dc.subject.lcsh	Small interfering RNA--Research
dc.subject.lcsh	Small interfering RNA--Therapeutic use--Research
dc.subject.lcsh	RNA interference--Research
dc.title	Explorations of siRNA therapeutics using molecular dynamics simulations: structural impacts of 2'-ribose modifications on RNA duplex and interactions with human Argonaute-2
dc.type	Thesis