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Alfredo Berzal-Herranz     Research Director 
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Alfredo Berzal-Herranz published an article in March 2019.
Research Keywords & Expertise
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Top co-authors See all
Carlos Briones

153 shared publications

Laboratory of Molecular Evolution, Centro de Astrobiología (CSIC-INTA), Torrejón de Ardoz, 28850 Madrid, Spain

Manuel Espinosa

101 shared publications

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain

Gloria H. Del Solar

45 shared publications

Centro de Investigaciones Biologicas, CSIC, Madrid, Spain

Wolfgang Nellen

37 shared publications

Abteilung Genetik, Universität Kassel, Kassel, Deutschland

Georg Sczakiel

21 shared publications

Institut für Molekulare Medizin; Universitätsklinikum Schleswig-Holstein; Universität zu Lübeck; Ratzeburger Allee 160 23538 Lübeck Germany

77
Publications
76
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361
Citations
Publication Record
Distribution of Articles published per year 
(1991 - 2017)
Total number of journals
published in
 
30
 
Publications See all
Article 0 Reads 0 Citations Potential of the Other Genetic Information Coded by the Viral RNA Genomes as Antiviral Target Alfredo Berzal-Herranz, Cristina Romero-López, Beatriz Berza... Published: 13 March 2019
Pharmaceuticals, doi: 10.3390/ph12010038
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In addition to the protein coding information, viral RNA genomes code functional information in structurally conserved units termed functional RNA domains. These RNA domains play essential roles in the viral cycle (e.g., replication and translation). Understanding the molecular mechanisms behind their function is essential to understanding the viral infective cycle. Further, interfering with the function of the genomic RNA domains offers a potential means of developing antiviral strategies. Aptamers are good candidates for targeting structural RNA domains. Besides its potential as therapeutics, aptamers also provide an excellent tool for investigating the functionality of RNA domains in viral genomes. This review briefly summarizes the work carried out in our laboratory aimed at the structural and functional characterization of the hepatitis C virus (HCV) genomic RNA domains. It also describes the efforts we carried out for the development of antiviral aptamers targeting specific genomic domains of the HCV and the human immunodeficiency virus type-1 (HIV-1).
Article 2 Reads 2 Citations The HCV genome domains 5BSL3.1 and 5BSL3.3 act as managers of translation Cristina Romero-López, Pablo Ríos-Marco, Beatriz Berzal-Herr... Published: 31 October 2018
Scientific Reports, doi: 10.1038/s41598-018-34422-7
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
The RNA genome of the hepatitis C virus (HCV) encodes a single open reading frame (ORF) containing numerous functional elements. Among these, the cis-acting replication element (CRE) at the 3′ end of the viral ORF, has become of increasing interest given its dual role as a viral translation repressor and replication enhancer. Long-range RNA-RNA contacts mediated by the CRE build the structural scaffold required for its proper functioning. The recruitment of different cellular factors, many related to the functioning of the translation machinery, might aid in the CRE-exerted downregulation of viral translation. The present data show that the CRE promotes a defect in polysome production, and hinders the assembly of the 80S complex, likely through the direct, high affinity recruitment of the 40S ribosomal subunit. This interaction involves the highly conserved 5BSL3.1 and 5BSL3.3 domains of the CRE, and is strictly dependent on RNA-protein contacts, particularly with the ribosomal proteins RPSA and RPS29. These observations support a model in which the CRE-mediated inhibition of viral translation is a multifactorial process defined by the establishment of long-range RNA-RNA interactions between the 5′ and 3′ ends of the viral genome, the sequestration of the 40S subunit by the CRE, and the subsequent stalling of polysome elongation at the 3′ end of the ORF, all governed by the highly stable hairpin domains 5BSL3.1 and 5BSL3.3. The present data thus suggest a new managerial role in HCV translation for these 5BSL3.1 and 5BSL3.3 domains.
Article 0 Reads 1 Citation A Dual Interaction Between the 5′- and 3′-Ends of the Melon Necrotic Spot Virus (MNSV) RNA Genome Is Required for Effici... Manuel Miras, Ana M. Rodríguez-Hernández, Cristina Romero-Ló... Published: 09 May 2018
Frontiers in Plant Science, doi: 10.3389/fpls.2018.00625
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In eukaryotes, the formation of a 5′-cap and 3′-poly(A) dependent protein–protein bridge is required for translation of its mRNAs. In contrast, several plant virus RNA genomes lack both of these mRNA features, but instead have a 3′-CITE (for cap-independent translation enhancer), a RNA element present in their 3′-untranslated region that recruits translation initiation factors and is able to control its cap-independent translation. For several 3′-CITEs, direct RNA-RNA long-distance interactions based on sequence complementarity between the 5′- and 3′-ends are required for efficient translation, as they bring the translation initiation factors bound to the 3′-CITE to the 5′-end. For the carmovirus melon necrotic spot virus (MNSV), a 3′-CITE has been identified, and the presence of its 5′-end in cis has been shown to be required for its activity. Here, we analyze the secondary structure of the 5′-end of the MNSV RNA genome and identify two highly conserved nucleotide sequence stretches that are complementary to the apical loop of its 3′-CITE. In in vivo cap-independent translation assays with mutant constructs, by disrupting and restoring sequence complementarity, we show that the interaction between the 3′-CITE and at least one complementary sequence in the 5′-end is essential for virus RNA translation, although efficient virus translation and multiplication requires both connections. The complementary sequence stretches are invariant in all MNSV isolates, suggesting that the dual 5′–3′ RNA:RNA interactions are required for optimal MNSV cap-independent translation and multiplication.
CONFERENCE-ARTICLE 15 Reads 0 Citations <strong>Multivalent Engineered RNA Molecules that Interfere with Hepatitis C Virus Translation and Replication</strong> Cristina Romero-López, Thomas Lahlali, Beatriz Berzal-Herran... Published: 01 November 2017
Proceedings of 3rd International Electronic Conference on Medicinal Chemistry, doi: 10.3390/ecmc-3-04654
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The design of novel and efficient compounds fighting against the highly variable RNA viruses, such as hepatitis C virus (HCV), is a major goal. RNA oligonucleotides have gained great interest as specific molecular tools for inhibiting essential viral processes. The combination of different RNA molecules with proven antiviral activity, each with its own activity and specificity, into a single molecule yields the so-called multivalent compounds, which are promising candidates for the development of new therapeutic strategies. These compounds are chimeric entities with enhanced therapeutic properties. In this work, the previously developed chimeric inhibitor RNA HH363-10 was used as archetype for the development of improved anti-HCV inhibitors. HH363-10 consists of a hammerhead ribozyme domain, targeting the essential internal ribosome entry site (IRES) region in the 5’ end of the HCV genome; and an aptamer RNA molecule, directed against the highly conserved IIIf domain of the IRES. As a result of the application of an in vitro selection process to the RNA pool, which results from the partial randomization of the aptamer-domain sequence of the HH363-10 molecule, 10 new multivalent optimized chimeric antiHCV RNA molecules were selected for further analysis. The aptamer RNA domain was evolved to contain two binding sites: the one mapping the IIIf domain, and a newly acquired targeting site, either to the IRES domain IV (which contains the translation start codon) or the essential linker region between the IRES domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC50 values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved, multivalent RNA molecules with potential clinical applications.

Article 4 Reads 4 Citations The 5BSL3.2 Functional RNA Domain Connects Distant Regions in the Hepatitis C Virus Genome Cristina Romero-López, Alfredo Berzal-Herranz Published: 31 October 2017
Frontiers in Microbiology, doi: 10.3389/fmicb.2017.02093
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Viral genomes are complexly folded entities that carry all the information required for the infective cycle. The nucleotide sequence of the RNA virus genome encodes proteins and functional information contained in discrete, highly conserved structural units. These so-called functional RNA domains play essential roles in the progression of infection, which requires their preservation from one generation to the next. Numerous functional RNA domains exist in the genome of the hepatitis C virus (HCV). Among them, the 5BSL3.2 domain in the cis-acting replication element (CRE) at the 3′ end of the viral open reading frame has become of particular interest given its role in HCV RNA replication and as a regulator of viral protein synthesis. These functionalities are achieved via the establishment of a complex network of long-distance RNA–RNA contacts involving (at least as known to date) the highly conserved 3′X tail, the apical loop of domain IIId in the internal ribosome entry site, and/or the so-called Alt region upstream of the CRE. Changing contacts promotes the execution of different stages of the viral cycle. The 5BSL3.2 domain thus operates at the core of a system that governs the progression of HCV infection. This review summarizes our knowledge of the long-range RNA–RNA interaction network in the HCV genome, with special attention paid to the structural and functional consequences derived from the establishment of different contacts. The potential implications of such interactions in switching between the different stages of the viral cycle are discussed.
Article 3 Reads 4 Citations Development of Optimized Inhibitor RNAs Allowing Multisite-Targeting of the HCV Genome Cristina Romero-López, Thomas Lahlali, Beatriz Berzal-Herran... Published: 22 May 2017
Molecules, doi: 10.3390/molecules22050861
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Engineered multivalent drugs are promising candidates for fighting infection by highly variable viruses, such as HCV. The combination into a single molecule of more than one inhibitory domain, each with its own target specificity and even a different mechanism of action, results in drugs with potentially enhanced therapeutic properties. In the present work, the anti-HCV chimeric inhibitor RNA HH363-10, which has a hammerhead catalytic domain and an aptamer RNA domain, was subjected to an in vitro selection strategy to isolate ten different optimised chimeric inhibitor RNAs. The catalytic domain was preserved while the aptamer RNA domain was evolved to contain two binding sites, one mapping to the highly conserved IIIf domain of the HCV genome’s internal ribosome entry site (IRES), and the other either to IRES domain IV (which contains the translation start codon) or the essential linker region between domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC50 values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved RNA molecules with potential clinical applications.
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