Conformational Dynamics of the Hepatitis B Virus Pre-genomic RNA on Multiple Time Scales: Implications for Viral Replication

Olenginski, Lukasz T.; Kasprzak, Wojciech K.; Bergonzo, Christina; Shapiro, Bruce A.; Dayie, T. Kwaku

doi:10.1016/j.jmb.2022.167633

Cited by 5 publications

(21 citation statements)

References 82 publications

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“…Computational predictions [ 31 ] further support this notion, suggesting that the most probable ligand cavity within ε is its PL ( Figure 1 c). In agreement with this hypothesis, we identified Raloxifene and other selective estrogen receptor modulators (SERMs) as the first class of ε-targeting ligands [ 30 ] that selectively bind FL ε at its flexible [ 30 , 32 ] PL ( Figure 1 d). Given that the PL is required for P binding [ 33 , 34 ], pgRNA–P packaging [ 22 , 23 , 27 , 29 , 33 , 34 ], and reverse transcription [ 27 , 29 , 33 ] ( Figure 1 a), ligands that target this motif may have an inhibitory effect.…”

Section: Introductionsupporting

confidence: 62%

“…To model the FL ε–Daclatasvir interaction, we employed computational docking and molecular dynamics (MD) simulations. Taken together, our data demonstrate that Daclatasvir selectively targets FL ε at its flexible [ 30 , 32 ] PL and modulates its dynamics. Given the functional importance of the PL [ 22 , 23 , 27 , 29 , 33 , 34 ] ( Figure 1 a), our work supports the notion that targeting ε dynamics may be an effective anti-HBV therapeutic strategy.…”

Section: Introductionsupporting

confidence: 55%

“…However, VS is not without limitations, especially when targeting RNA. For example, docking to RNA targets is complicated for flexible RNAs such as FL ε [ 30 , 32 ] and ligand-induced conformational changes. One approach to overcome this challenge is to treat the RNA target as a conformational ensemble that is then subject to VS [ 36 , 37 , 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…Unfortunately, these data are sparse for FL ε [ 30 ] due to its large size. To partially address the inherent dynamics [ 30 , 32 ] of FL ε, we instead used a rigid dock VS, followed by MD simulations.…”

Section: Resultsmentioning

confidence: 99%

“…As a way to partially address the inherent dynamics [ 30 , 32 ] of FL ε, we carried out 500 ns MD simulations on FL ε R3 and the FL ε R3–Daclatasvir complex with the top-scored pose derived from RNAPosers. In the latter trajectory, Daclatasvir remained stably bound to the RNA target at its PL and the upper part of the LH ( Figure 6 b), further suggesting a valid docking pose prediction ( Figure 6 a), and in agreement with our interpretation of the dye-displacement ( Figure 5 b) and NMR titration ( Figure 5 c) data ( Figure S7 ).…”

Section: Resultsmentioning

confidence: 99%

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Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target

et al. 2023

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The global burden imposed by hepatitis B virus (HBV) infection necessitates the discovery and design of novel antiviral drugs to complement existing treatments. One attractive and underexploited therapeutic target is ε, an ~85-nucleotide (nt) cis-acting regulatory stem-loop RNA located at the 3′- and 5′-ends of the pre-genomic RNA (pgRNA). Binding of the 5′-end ε to the viral polymerase protein (P) triggers two early events in HBV replication: pgRNA and P packaging and reverse transcription. Our recent solution nuclear magnetic resonance spectroscopy structure of ε permits structure-informed drug discovery efforts that are currently lacking for P. Here, we employ a virtual screen against ε using a Food and Drug Administration (FDA)-approved compound library, followed by in vitro binding assays. This approach revealed that the anti-hepatitis C virus drug Daclatasvir is a selective ε-targeting ligand. Additional molecular dynamics simulations demonstrated that Daclatasvir targets ε at its flexible 6-nt priming loop (PL) bulge and modulates its dynamics. Given the functional importance of the PL, our work supports the notion that targeting ε dynamics may be an effective anti-HBV therapeutic strategy.

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Section: Introductionsupporting

confidence: 62%

Section: Introductionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target

et al. 2023

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Regulatory Mechanisms through RNA Conformational Switching and Dynamics

Bevilacqua

Tolbert

2022

Journal of Molecular Biology

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Nuclear spin relaxation

Kowalewski

2023

Nuclear Magnetic Resonance

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This review covers the progress in the field of NMR relaxation in fluids during 2022. The emphasis is on comparatively simple liquids and solutions of physico-chemical and chemical interest, in analogy with the previous periods, but selected biophysics-related topics (here, I also include some work on relaxation in solid biomaterials) and relaxation-related studies on more complex systems (macromolecular solutions, liquid crystalline systems, glassy and porous materials) are also covered. Section 2 of the chapter is concerned with general, physical and experimental aspects of nuclear spin relaxation, while Section 3 is concentrated on applications.

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Conformational Dynamics of the Hepatitis B Virus Pre-genomic RNA on Multiple Time Scales: Implications for Viral Replication

Cited by 5 publications

References 82 publications

Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target

Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target

Regulatory Mechanisms through RNA Conformational Switching and Dynamics

Nuclear spin relaxation

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