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RNA: Still an Under-Exploited Drug Target
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RNA: Still an Under-Exploited Drug Target

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 November 2021) | Viewed by 11453

Special Issue Editor

Prof. Dr. Oriana Tabarrini

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
Interests: HIV; influenza; tuberculosis; SARS-CoV-2; PARPs; small molecules; protein–protein interaction

Special Issue Information

Dear Colleagues,

The classical view of RNA as a passive carrier of genetic information has been replaced by a new vision with an expanded role for RNA transcripts as key regulators of diverse biological phenome with a number of vital roles in the cell. Only 3% of RNA transcripts code for protein, while the vast majority of RNAs are noncoding RNA (ncRNA). Many lines of evidence are linking mutations and dysregulations of ncRNAs to a host of human diseases, such as Huntington's disease, six spinocerebellar ataxias, and other neurodegenerative diseases. RNA can also adopt a non-canonical higher-order structure called G-quadruplexes that are found in oncogene promoters, telomeres, and introns of mRNAs. These regions have been recognized as potential targets for anticancer drugs. In the non-mammalian system, highly conserved ncRNAs have also been emerging as new opportunities to expand the repertoire of drug targets, such as the well-known rRNA, and also TAR RNA and RRE RNA from HIV-1, and the IRES from HCV. Viruses for which targeting ncRNA components in the genome or transcripts may be promising also include SARS CoV, influenza A, Dengue, Zika, and West Nile. RNA mimics proteins, in that it folds into intricate hydrophilic three-dimensional pockets and can interconvert into multiple related conformations, providing multiple opportunities for binding by selective small molecules. Contributions to this Special Issue, in the form of original research or review articles, may cover any aspect of drug discovery aimed at identifying small molecules that, through a different mechanism of action, recognize the various species of RNA. Work aimed at defining the mechanism of RNA–protein interactions, as well as the emerging strategies to develop new tools for designing and screening RNA-targeted small molecules, are also welcome.

Prof. Oriana Tabarrini
Guest Editor

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Keywords

  • RNA as a target for infectious diseases
  • RNA as a target for neurodegenerative diseases
  • RNA as a target for cancer diseases
  • New methodologies in designing/assaying RNA-targeted small molecules

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Published Papers (3 papers)

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Research

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12 pages, 2507 KiB  
Article
Bis-3-Chloropiperidines Targeting TAR RNA as A Novel Strategy to Impair the HIV-1 Nucleocapsid Protein
by Alice Sosic, Giulia Olivato, Caterina Carraro, Richard Göttlich, Dan Fabris and Barbara Gatto
Molecules 2021, 26(7), 1874; https://doi.org/10.3390/molecules26071874 - 26 Mar 2021
Cited by 10 | Viewed by 2416
Abstract
Specific RNA sequences regulate functions essential to life. The Trans-Activation Response element (TAR) is an RNA stem–bulge–loop structure involved in several steps of HIV-1 replication. In this work, we show how RNA targeting can inhibit HIV-1 nucleocapsid (NC), a highly conserved protein known [...] Read more.
Specific RNA sequences regulate functions essential to life. The Trans-Activation Response element (TAR) is an RNA stem–bulge–loop structure involved in several steps of HIV-1 replication. In this work, we show how RNA targeting can inhibit HIV-1 nucleocapsid (NC), a highly conserved protein known to catalyze nucleic acid melting and strand transfers during reverse transcription. Our RNA targeting strategy consists of the employment of bis-3-chloropiperidines (B-CePs) to impair RNA melting through bifunctional alkylation. Specific interactions between B-CePs and TAR RNA were analytically investigated by gel electrophoresis and mass spectrometry, allowing the elucidation of B-CePs’ recognition of TAR, and highlighting an RNA-directed mechanism of protein inhibition. We propose that B-CePs can freeze TAR tridimensional conformation, impairing NC-induced dynamics and finally inhibiting its functions in vitro. Full article
(This article belongs to the Special Issue RNA: Still an Under-Exploited Drug Target)
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14 pages, 2834 KiB  
Article
3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis
by Ellen Bak, Jennifer T. Miller, Andrea Noronha, John Tavis, Emilio Gallicchio, Ryan P. Murelli and Stuart F. J. Le Grice
Molecules 2020, 25(19), 4434; https://doi.org/10.3390/molecules25194434 - 27 Sep 2020
Cited by 11 | Viewed by 3617
Abstract
Initiation of protein-primed (-) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral reverse transcriptase with epsilon (ε), a cis-acting regulatory signal located at the 5’ terminus of pre-genomic RNA (pgRNA), and several host-encoded chaperone proteins. Binding of [...] Read more.
Initiation of protein-primed (-) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral reverse transcriptase with epsilon (ε), a cis-acting regulatory signal located at the 5’ terminus of pre-genomic RNA (pgRNA), and several host-encoded chaperone proteins. Binding of the viral polymerase (P protein) to ε is necessary for pgRNA encapsidation and synthesis of a short primer covalently attached to its terminal domain. Although we identified small molecules that recognize HBV ε RNA, these failed to inhibit protein-primed DNA synthesis. However, since initiation of HBV (-) strand DNA synthesis occurs within a complex of viral and host components (e.g., Hsp90, DDX3 and APOBEC3G), we considered an alternative therapeutic strategy of allosteric inhibition by disrupting the initiation complex or modifying its topology. To this end, we show here that 3,7-dihydroxytropolones (3,7-dHTs) can inhibit HBV protein-primed DNA synthesis. Since DNA polymerase activity of a ribonuclease (RNase H)-deficient HBV reverse transcriptase that otherwise retains DNA polymerase function is also abrogated, this eliminates direct involvement of RNase (ribonuclease) H activity of HBV reverse transcriptase and supports the notion that the HBV initiation complex might be therapeutically targeted. Modeling studies also provide a rationale for preferential activity of 3,7-dHTs over structurally related α-hydroxytropolones (α-HTs). Full article
(This article belongs to the Special Issue RNA: Still an Under-Exploited Drug Target)
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Review

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12 pages, 9963 KiB  
Review
Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding
by Daria V. Berdnikova, Paolo Carloni, Sybille Krauß and Giulia Rossetti
Molecules 2021, 26(11), 3384; https://doi.org/10.3390/molecules26113384 - 3 Jun 2021
Cited by 6 | Viewed by 4529
Abstract
Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics [...] Read more.
Aberrant RNA–protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA–protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy. Full article
(This article belongs to the Special Issue RNA: Still an Under-Exploited Drug Target)
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