
Jose GallegoValencia Catholic University Saint Vincent Martyr
Jose Gallego
Ph.D. Pharmacy
About
55
Publications
5,532
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
1,682
Citations
Introduction
Additional affiliations
November 2004 - December 2009
Publications
Publications (55)
The programmed ribosomal frameshift (PRF) region is found in the RNA genome of all coronaviruses and shifts the ribosome reading frame through formation of a three-stem pseudoknot structure, allowing the translation of essential viral proteins. Using NMR spectroscopy, comparative sequence analyses and functional assays we show that, in the absence...
Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to...
The complex between the Rev protein of HIV-1 and the Rev Recognition Element (RRE) within the virus RNA promotes nuclear export of unspliced or incompletely spliced viral transcripts and is required for virus transmission. Here, we have screened a virtual collection of compounds using a pharmacophore based on the chemical similarity of previously c...
Antiviral agents are needed for the treatment of SARS-CoV-2 infections and to control other coronavirus outbreaks that may occur in the future. Here we report the identification and characterization of RNA-binding compounds that inhibit SARS-CoV-2 replication. The compounds were detected by screening a small library of antiviral compounds previousl...
Structures of well-folded RNA molecules can be determined with atomic resolution by either X-ray crystallography, cryo-EM, or NMR spectroscopy, but those of conformationally-flexible RNAs often are difficult to study with these methods. However, flexible RNAs have biological relevance and likely represent the majority of the RNA conformational spac...
New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry site. The conformational effect of...
Subdomain 5BSL3.2 of hepatitis C virus RNA lies at the core of a network of distal RNA–RNA contacts that connect the 5′ and 3′ regions of the viral genome and regulate the translation and replication stages of the viral cycle. Using small-angle X-ray scattering and NMR spectroscopy experiments, we have determined at low resolution the structural mo...
The current pandemic situation caused by the Be-tacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, struc-tured RNA elements represent a potent alternative as drug targets. The search for drugs that target R...
Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally...
The 3'X domain of hepatitis C virus has been reported to control viral replication and translation by modulating the exposure of a nucleotide segment involved in a distal base-pairing interaction with an upstream 5BSL3.2 domain. To study the mechanism of this molecular switch, we have analysed the structure of 3'X mutants that favour one of the two...
The SUS1 gene of Saccharomyces cerevisiae is unusual as it contains two introns and undergoes alternative splicing, retaining one or both introns depending on growth conditions. The exon located between the two introns can be skipped during splicing and has been detected in circular form. This exon (E2) has also been found to influence the splicing...
The Rev protein of HIV-1 binds to the Rev Recognition Element (RRE) in the virus RNA to promote nuclear export of unspliced and partially spliced transcripts, an essential step in the virus transmission cycle. Here, we describe the screening of a library of chemically diverse compounds with an assay based on monitoring the interaction between the R...
The 3'X tail is a functionally essential 98-nt sequence located at the 3'-end of the hepatitis C virus (HCV) RNA genome. The domain contains two absolutely conserved dimer linkage sequence (DLS) and k nucleotide segments involved in viral RNA dimerization and in a distal base-pairing interaction with stem-loop 5BSL3.2, respectively. We have previou...
The 3'X domain is a 98-nucleotide region located at the 3' end of hepatitis C virus genomic RNA that plays essential functions in the viral life cycle. It contains an absolutely conserved, 16-base palindromic sequence that promotes viral RNA dimerization, overlapped with a 7-nucleotide tract implicated in a distal contact with a nearby functional s...
Sus1 is a conserved protein involved in chromatin remodeling and mRNA biogenesis. Unlike most yeast genes, the SUS1 pre-mRNA of Saccharomyces cerevisiae contains two introns and is alternatively spliced, retaining one or both introns in response to changes in environmental conditions. SUS1 splicing may allow the cell to control Sus1 expression, but...
The 3'X domain of hepatitis C virus is a strongly conserved structure located at the 3' terminus of the viral genomic RNA. This domain modulates the replication and translation processes of the virus in conjunction with an upstream 5BSL3.2 stem-loop, and contains a palindromic sequence that facilitates RNA dimerization. Based on nuclear magnetic re...
Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is an inborn error of the urea cycle having autosomal (2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 d...
Rev(ersing) RNA binding: RNA-binding inhibitors based on a bilaterally substituted p-terphenylene scaffold (green) project their substituents in a broad spatial angle and reproduce the interactions of a protein α-helix (red) embedded in its RNA receptor. These terphenyls can mimic one α-helix of the HIV-1 protein Rev and inhibit Rev function and HI...
Bilaterally substituted p‐terphenyl molecules reproduce the interactions of an α‐helix of the HIV‐1 protein Rev with its RNA receptor and block Rev function and virus replication. In their Communication on page 13405 ff., J. Alcamí, S. Fustero, and J. Gallego et al. report the structure‐based design of p‐terphenyl molecules that inhibit the Rev‐med...
RNA‐bindende Inhibitoren mit einem bilateral substituierten p‐Terphenylengerüst (grün) projizieren ihre Substituenten in einem breiten Winkelbereich und reproduzieren die Wechselwirkungen einer in ihren RNA‐Rezeptor eingebetteten Protein‐α‐Helix (rot). Diese Terphenyle können eine α‐Helix des HIV‐1‐Proteins Rev nachahmen und inhibieren die Funktion...
Beidseitig substituierte p‐Terphenylmoleküle reproduzieren die Wechselwirkungen einer α‐Helix des HIV‐1‐Proteins Rev mit seinem RNA‐Rezeptor und blockieren die Rev‐Funktion und Virusreplikation. J. Alcamí, S. Fustero, J. Gallego et al. stellen in ihrer Zuschrift auf S. 13647 ff. das strukturbasierte Design von p‐Terphenylmolekülen vor, die den Rev‐...
The bisnaphthalimide cytotoxic agent elinafide exhibits a mixed DNA binding mode including groove-association and intercalation. We have compared the interaction of elinafide and two bisnaphthalimide analogues with various natural and modified DNA sequences using solution NMR and UV-melting methods and surface plasmon resonance (SPR) experiments at...
Transmissible gastroenteritis coronavirus (TGEV) genomic RNA transcription generates 5′- and 3′-coterminal subgenomic mRNAs.
This process involves a discontinuous step during the synthesis of minus-sense RNA that is modulated by transcription-regulating
sequences located at the 3′ end of the leader (TRS-L) and also preceding each viral gene (TRS-Bs...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Proline, the feedback inhibitor of bacterial glutamate kinase (GK) and plant pyrroline-5-carboxylate synthase (P5CS) enzymes, is a key regulator of the osmotic and redox balance of cells. Using kinetic assays, site-directed mutagenesis, structure-activity analyses, and docking calculations, we have identified the binding site of this metabolite in...
Three-way junction RNAs adopt a recurrent Y shape when two of the helices form a coaxial stack and the third helix establishes one or more tertiary contacts several base pairs away from the junction. In this review, the structure, distribution, and functional relevance of these motifs are examined. Structurally, the folds exhibit conserved junction...
NAG (N-acetyl-L-glutamate), the essential allosteric activator of the first urea cycle enzyme, CPSI (carbamoyl phosphate synthetase I), is a key regulator of this crucial cycle for ammonia detoxification in animals (including humans). Automated cavity searching and flexible docking have allowed identification of the NAG site in the crystal structur...
Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favorable substrate properties, their discovery has remained challenging. Here we describe a complementa...
The sequence-specific structural and dynamic properties of double-helical DNA play important roles in many biological processes involving DNA recognition. Using a combination of NMR spectroscopy, surface plasmon resonance, and UV thermal denaturation experiments, we have investigated how sequences not making direct contact with the drug modulate th...
Loop–loop tertiary interactions play a key role in the folding and catalytic activity of natural hammerhead ribozymes. Using
a combination of NMR spectroscopy, site-directed mutagenesis and kinetic and infectivity analyses, we have examined the structure
and function of loops 1 and 2 of the (+) and (–) hammerheads of chrysanthemum chlorotic mottle...
The pseudouridine synthase and archaeosine transglycosylase (PUA) domain is a compact and highly conserved RNA-binding motif that is widespread among diverse types of proteins from the three kingdoms of life. Its three-dimensional architecture is well established, and the structures of several PUA-RNA complexes reveal a common RNA recognition surfa...
Universal bases hybridize with all other natural DNA or RNA bases, and have applications in PCR and sequencing. We have analysed
by nuclear magnetic resonance spectroscopy the structure and dynamics of three DNA oligonucleotides containing the universal
base analogues 5-nitroindole and 5-nitroindole-3-carboxamide. In all systems studied, both the 5...
Bisnaphthalimide intercalators are anti-tumour agents composed of two planar rings linked by a flexible diazanonylene chain.
The intercalated rings of three bisnaphthalimide analogues complexed to DNA are found here to undergo 180° rotating motions
that do not affect the diazanonylene linker atoms bound to the major groove. These ring rotations are...
The leader RNA sequence of human immunodeficiency virus type 1 (HIV-1) consists of a complex series of stem loop structures
that are critical for viral replication. Three-dimensional structural analysis by NMR of one of these structures, the SL1
stem loop of the packaging signal region, revealed a highly conserved purine rich loop with a structure...
Many virus species, as well as a limited number of cellular mRNAs, initiate protein synthesis by an unusual mechanism, based on well-defined RNA structures called internal ribosome entry sites (IRES). IRES-mediated internal initiation allows recognition of the start codon by the ribosome in a cap-independent way, avoiding major regulatory steps. Th...
The packaging signal (Psi) of the human immunodeficiency virus type 1 (HIV-1) enables encapsidation of the full-length genomic RNA against a background of a vast excess of cellular mRNAs. The core HIV-1 Psi is approximately 109 nucleotides and contains sequences critical for viral genomic dimerisation and splicing, in addition to the packaging sign...
The hepatitis C virus (HCV) internal ribosome entry site (IRES) is recognized specifically by the small ribosomal subunit and eukaryotic initiation factor 3 (eIF3) before viral translation initiation. Using extensive mutagenesis and structure probing analysis, we show that the eIF3-binding domain of the HCV IRES contains an internal loop structure...
The hepatitis C virus (HCV) is the main causative agent of non-A, non-B hepatitis in humans and a major cause of mortality and morbidity in the world. Currently there is no effective treatment available for the infection caused by this virus, whose replication depends on an unusual translation-initiation mechanism. The viral RNA contains an interna...
Transcriptional termination by RNA polymerase I1 depends on both poly(A) signals, their associated RNA processing factors and downstream transcriptional pause sites. 1) In Scerevisiae we are investigating the role of transcriptional termination in the prevention of transcriptional interference between adjacent genes. This problem may be especially...
Researchers' increasing awareness of the essential role played by RNA in many biological processes and in the progression of disease makes the discovery of new RNA targets an emerging field in drug discovery. Since most existing pharmacologically active compounds bind proteins, RNA provides nearly untapped opportunities for pharmacological developm...
Using a combination of nuclear magnetic resonance (NMR) spectroscopy experiments and molecular dynamics, we have analyzed the structure and dynamics of a complex between the bisnaphthalimide drug LU-79553 and the DNA duplex d(ATGCAT)(2), LU-79553 is a DNA-binding topoisomerase II inhibitor that is particularly effective against human solid tumors t...
We have carried out a physicochemical and computational analysis on the stability of the intercalated structures formed by cytosine-rich DNA strands. In the computational study, the electrostatic energy components have been calculated using a Poisson-Boltzmann model, and the non-polar energy components have been computed with a van der Waals functi...
The solution structures of the oligodeoxynucleotides d(CCCGTTTCC) and d(TCCCGTTTCCA) have been determined by two-dimensional NMR spectroscopy. These oligomers are part of a DNA box in human centromeric alpha satellite targeted by the centromere protein B (CENP-B). Both CENP-B and its recognition box in alphoid DNA are conserved in mammals, suggesti...
Molecular models of the complexes between actinomycin D and 14 different DNA hexamers were built based on the X-ray crystal structure of the actinomycin-d(GAAGCTTC)2 complex. The DNA sequences included the canonical GpC binding step flanked by different base pairs, nonclassical binding sites such as GpG and GpT, and sites containing 2,6-diamino-pur...
The X-ray crystal structures of the complexes of ditercalinium and Flexi-Di with d(CGCG)2 have been studied by computational chemistry methods in an attempt to rationalize their distinct structural features. In addition, the complexes of these two bisintercalating drugs with d(GCGCGC)2 have been modeled and subjected to 0.5 ns of molecular dynamics...
Molecular dynamics simulations have been used to explore the behavior of the complexes of echinomycin with the DNA tetramers d(GCGC)2 and d(CCGG)2 in which the terminal bases have been paired according to either a Hoogsteen or a Watson-Crick hydrogen bonding scheme. The energy of the four resulting complexes has been monitored along the dynamics tr...
The binding of echinomycin to DNA hexamers of the form GpApXpZpTpC, where the central XpZ step can be CpG, TpA, GpC, or ApT, has been studied by molecular modeling and molecular mechanics techniques. Interaction energies have also been calculated for the complexation of echinomycin with sequences containing the preferred central CpG step and differ...
The behavior of the complexes of echinomycin with the DNA tetramers d(ACGT)2 and d(TCGA)2, in which the terminal AT base pairs are in either a Hoogsteen or a Watson-Crick conformation, has been explored by molecular dynamics taking into account experimental data from NMR studies (Gao and Patel. Biochemistry 1988, 27, 1744-1751). The DNA binding spe...
A model structure of Naja naja kaouthia cobra venom phospholipase A2 has been constructed by utilizing molecular modeling techniques. Analysis of the model and available biochemical data reveal the presence in this enzyme of a putative recognition site for choline derivatives in loop 57-70 made up of residues Trp-61, Tyr-63, Phe-64, and Lys-65, tog...