Enhancing the ligand efficiency of anti-HIV compounds targeting frameshift-stimulating RNA

Anokhina, Viktoriya; McAnany, John D.; Ciesla, Jessica H.; Hilimire, Thomas A.; Santoso, Netty; Miao, Hongyu; Miller, Benjamin L.

doi:10.1016/j.bmc.2019.05.009

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…The discovery that a packaging-defective MHV mutant was markedly suppressed by host innate immunity suggests an attractive pathway toward live-attenuated vaccine design (Athmer et al, 2018). The PS itself may also become a candidate for therapeutic intervention as RNA structures are being increasingly developed as small-molecule druggable targets (Anokhina et al, 2019;Ingemarsdotter et al, 2018). Additionally, more precise elucidation of packaging-specific oligomeric interactions could uncover molecular targets that would hinder the escape of drug-resistant viral mutants (Tanner et al, 2014).…”

Section: Future Perspectivesmentioning

confidence: 99%

Coronavirus genomic RNA packaging

2019

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RNA viruses carry out selective packaging of their genomes in a variety of ways, many involving a genomic packaging signal. The first coronavirus packaging signal was discovered nearly thirty years ago, but how it functions remains incompletely understood. This review addresses the current state of knowledge of coronavirus genome packaging, which has mainly been studied in two prototype species, mouse hepatitis virus and transmissible gastroenteritis virus. Despite the progress that has been made in the mapping and characterization of some packaging signals, there is conflicting evidence as to whether the viral nucleocapsid protein or the membrane protein plays the primary role in packaging signal recognition. The different models for the mechanism of genomic RNA packaging that have been prompted by these competing views are described. Also discussed is the recent exciting discovery that selective coronavirus genome packaging is critical for in vivo evasion of the host innate immune response.

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Section: Future Perspectivesmentioning

confidence: 99%

Coronavirus genomic RNA packaging

2019

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“…-1PRF in retroviruses (HIV) and alphaviruses (SFV) seems to be suppressed by this protein, which is thought to bind to both the translating ribosome and the frameshifting mRNA motif by a mechanism that is not fully understood (93). Multiple attempts have been made to design synthetic drugs targeting the frameshifting motif of HIV-1 (121)(122)(123)(124)(125) and SARS coronavirus (126). Recently, Matsumoto et al have developed a small-molecule tool that can induce pseudoknot formation and activate -1PRF both in vitro and in vivo in human cells (127).…”

Section: Spontaneous and Programmed Ribosome Frameshiftingmentioning

confidence: 99%

Translational recoding: canonical translation mechanisms reinterpreted

Rodnina

Korniy

Klimova

et al. 2019

Nucleic Acids Research

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During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and the protein sequence is essential for the quality of the cellular proteome. Spontaneous errors in decoding or translocation are rare and result in a deficient protein. However, dedicated recoding signals in the mRNA can reprogram the ribosome to read the message in alternative ways. This review summarizes the recent advances in understanding the mechanisms of three types of recoding events: stop-codon readthrough, -1 ribosome frameshifting and translational bypassing. Recoding events provide insights into alternative modes of ribosome dynamics that are potentially applicable to other non-canonical modes of prokaryotic and eukaryotic translation.

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“…Indeed, work on other viruses has found more generally that −1 PRF levels must typically be held within a relatively narrow range to avoid attenuation [ 7 , 8 ]. As a result, frameshift-stimulatory structures are potential targets for anti-viral drugs [ [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot

Neupane

Munshi

Zhao

et al. 2020

Journal of Molecular Biology

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SARS-CoV-2 uses −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins. Because modulating −1 PRF can attenuate the virus, ligands binding to the RNA pseudoknot that stimulates −1 PRF may have therapeutic potential. Mutations in the pseudoknot have occurred during the pandemic, but how they affect −1 PRF efficiency and ligand activity is unknown. Studying a panel of six mutations in key regions of the pseudoknot, we found that most did not change −1 PRF levels, even when base-pairing was disrupted, but one led to a striking 3-fold decrease, suggesting SARS-CoV-2 may be less sensitive to −1 PRF modulation than expected. Examining the effects of a small-molecule −1 PRF inhibitor active against SARS-CoV-2, it had a similar effect on all mutants tested, regardless of basal −1 PRF efficiency, indicating that anti-frameshifting activity can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of −1 PRF.

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Enhancing the ligand efficiency of anti-HIV compounds targeting frameshift-stimulating RNA

Cited by 12 publications

References 39 publications

Coronavirus genomic RNA packaging

Coronavirus genomic RNA packaging

Translational recoding: canonical translation mechanisms reinterpreted

Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot

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