Cargando…

Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)

Rhinoviruses (RVs) are the major cause of common cold, a respiratory disease that generally takes a mild course. However, occasionally, RV infection can lead to serious complications in patients debilitated by other ailments, e.g., asthma. Colds are a huge socioeconomic burden as neither vaccines no...

Descripción completa

Detalles Bibliográficos
Autores principales: Real-Hohn, Antonio, Groznica, Martin, Kontaxis, Georg, Zhu, Rong, Chaves, Otávio Augusto, Vazquez, Leonardo, Hinterdorfer, Peter, Kowalski, Heinrich, Blaas, Dieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141139/
https://www.ncbi.nlm.nih.gov/pubmed/37112983
http://dx.doi.org/10.3390/v15041003
_version_ 1785033321240068096
author Real-Hohn, Antonio
Groznica, Martin
Kontaxis, Georg
Zhu, Rong
Chaves, Otávio Augusto
Vazquez, Leonardo
Hinterdorfer, Peter
Kowalski, Heinrich
Blaas, Dieter
author_facet Real-Hohn, Antonio
Groznica, Martin
Kontaxis, Georg
Zhu, Rong
Chaves, Otávio Augusto
Vazquez, Leonardo
Hinterdorfer, Peter
Kowalski, Heinrich
Blaas, Dieter
author_sort Real-Hohn, Antonio
collection PubMed
description Rhinoviruses (RVs) are the major cause of common cold, a respiratory disease that generally takes a mild course. However, occasionally, RV infection can lead to serious complications in patients debilitated by other ailments, e.g., asthma. Colds are a huge socioeconomic burden as neither vaccines nor other treatments are available. The many existing drug candidates either stabilize the capsid or inhibit the viral RNA polymerase, the viral proteinases, or the functions of other non-structural viral proteins; however, none has been approved by the FDA. Focusing on the genomic RNA as a possible target for antivirals, we asked whether stabilizing RNA secondary structures might inhibit the viral replication cycle. These secondary structures include G-quadruplexes (GQs), which are guanine-rich sequence stretches forming planar guanine tetrads via Hoogsteen base pairing with two or more of them stacking on top of each other; a number of small molecular drug candidates increase the energy required for their unfolding. The propensity of G-quadruplex formation can be predicted with bioinformatics tools and is expressed as a GQ score. Synthetic RNA oligonucleotides derived from the RV-A2 genome with sequences corresponding to the highest and lowest GQ scores indeed exhibited characteristics of GQs. In vivo, the GQ-stabilizing compounds, pyridostatin and PhenDC3, interfered with viral uncoating in Na(+) but not in K(+)-containing phosphate buffers. The thermostability studies and ultrastructural imaging of protein-free viral RNA cores suggest that Na(+) keeps the encapsulated genome more open, allowing PDS and PhenDC3 to diffuse into the quasi-crystalline RNA and promote the formation and/or stabilization of GQs; the resulting conformational changes impair RNA unraveling and release from the virion. Preliminary reports have been published.
format Online
Article
Text
id pubmed-10141139
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-101411392023-04-29 Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+) Real-Hohn, Antonio Groznica, Martin Kontaxis, Georg Zhu, Rong Chaves, Otávio Augusto Vazquez, Leonardo Hinterdorfer, Peter Kowalski, Heinrich Blaas, Dieter Viruses Article Rhinoviruses (RVs) are the major cause of common cold, a respiratory disease that generally takes a mild course. However, occasionally, RV infection can lead to serious complications in patients debilitated by other ailments, e.g., asthma. Colds are a huge socioeconomic burden as neither vaccines nor other treatments are available. The many existing drug candidates either stabilize the capsid or inhibit the viral RNA polymerase, the viral proteinases, or the functions of other non-structural viral proteins; however, none has been approved by the FDA. Focusing on the genomic RNA as a possible target for antivirals, we asked whether stabilizing RNA secondary structures might inhibit the viral replication cycle. These secondary structures include G-quadruplexes (GQs), which are guanine-rich sequence stretches forming planar guanine tetrads via Hoogsteen base pairing with two or more of them stacking on top of each other; a number of small molecular drug candidates increase the energy required for their unfolding. The propensity of G-quadruplex formation can be predicted with bioinformatics tools and is expressed as a GQ score. Synthetic RNA oligonucleotides derived from the RV-A2 genome with sequences corresponding to the highest and lowest GQ scores indeed exhibited characteristics of GQs. In vivo, the GQ-stabilizing compounds, pyridostatin and PhenDC3, interfered with viral uncoating in Na(+) but not in K(+)-containing phosphate buffers. The thermostability studies and ultrastructural imaging of protein-free viral RNA cores suggest that Na(+) keeps the encapsulated genome more open, allowing PDS and PhenDC3 to diffuse into the quasi-crystalline RNA and promote the formation and/or stabilization of GQs; the resulting conformational changes impair RNA unraveling and release from the virion. Preliminary reports have been published. MDPI 2023-04-19 /pmc/articles/PMC10141139/ /pubmed/37112983 http://dx.doi.org/10.3390/v15041003 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Real-Hohn, Antonio
Groznica, Martin
Kontaxis, Georg
Zhu, Rong
Chaves, Otávio Augusto
Vazquez, Leonardo
Hinterdorfer, Peter
Kowalski, Heinrich
Blaas, Dieter
Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title_full Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title_fullStr Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title_full_unstemmed Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title_short Stabilization of the Quadruplex-Forming G-Rich Sequences in the Rhinovirus Genome Inhibits Uncoating—Role of Na(+) and K(+)
title_sort stabilization of the quadruplex-forming g-rich sequences in the rhinovirus genome inhibits uncoating—role of na(+) and k(+)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10141139/
https://www.ncbi.nlm.nih.gov/pubmed/37112983
http://dx.doi.org/10.3390/v15041003
work_keys_str_mv AT realhohnantonio stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT groznicamartin stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT kontaxisgeorg stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT zhurong stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT chavesotavioaugusto stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT vazquezleonardo stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT hinterdorferpeter stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT kowalskiheinrich stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk
AT blaasdieter stabilizationofthequadruplexforminggrichsequencesintherhinovirusgenomeinhibitsuncoatingroleofnaandk