Cybele Garcia - Academia.edu (original) (raw)

Papers by Cybele Garcia

Molecular Biology of the Cell, 2017

Viperin exerts antiviral function against Junin mammarenavirus at different subcellular localizat... more Viperin exerts antiviral function against Junin mammarenavirus at different subcellular localizations

Viruses

There is no specific chemotherapy approved for the treatment of pathogenic arenaviruses that caus... more There is no specific chemotherapy approved for the treatment of pathogenic arenaviruses that cause severe hemorrhagic fever (HF) in the population of endemic regions in America and Africa. The present study reports the effects of the natural flavonoid quercetin (QUER) on the infection of A549 and Vero cells with Junín virus (JUNV), agent of the Argentine HF. By infectivity assays, a very effective dose-dependent reduction of JUNV multiplication was shown by cell pretreatment at 2–6 h prior to the infection at non-cytotoxic concentrations, with 50% effective concentration values in the range of 6.1–7.5 µg/mL. QUER was also active by post-infection treatment but with minor efficacy. Mechanistic studies indicated that QUER mainly affected the early steps of virus adsorption and internalization in the multiplication cycle of JUNV. Treatment with QUER blocked the phosphorylation of Akt without changes in the total protein expression, detected by Western blot, and the consequent perturbat...

Microorganisms

Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-t... more Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses.

Biochemical and Biophysical Research Communications, 2022

The New World (NW) mammarenavirus Junín (JUNV) is the etiological agent of Argentine hemorrhagic ... more The New World (NW) mammarenavirus Junín (JUNV) is the etiological agent of Argentine hemorrhagic fever, a human endemic disease of Argentina. Promyelocytic leukemia protein (PML) has been reported as a restriction factor for several viruses although the mechanism/s behind PML-mediated antiviral effect may be diverse and are a matter of debate. Previous studies have reported a nuclear to cytoplasm translocation of PML during the murine Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) infection. This translocation was found to be mediated by the viral Z protein. Here, we show that PML restricts JUNV infection in human A549 cells. However, in contrast to LCVM, JUNV infection enhances PML expression and PML is not translocated to the cytoplasm neither it colocalizes with JUNV Z protein. Our study demonstrates that a NW mammarenavirus as JUNV interacts differently with the antiviral protein PML than LCMV.

Journal of Virology, 2022

aLaboratory of Pharmaceutical Biotechnology, Instituto de Biología y Medicina Experimental (IBYME... more aLaboratory of Pharmaceutical Biotechnology, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina bDepartment of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, University of California Los Angeles, Los Angeles, California, USA cLaboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), IQUIBICEN, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-UBA, Ciudad Universitaria, Buenos Aires, Argentina dDepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, USA eDepartment of Biological Chemistry and Department of Chemistry and Biochemistry, University of California Los Angeles, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, California, USA fDepartment of Medicine, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, USA gIQUIBICEN, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-UBA, Ciudad Universitaria, Buenos Aires, Argentina

Journal of Virology, 2021

Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. T... more Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil.

Reference Module in Biomedical Sciences, 2020

Methods in Molecular Biology, 2017

Among the members of the Arenaviridae family, Junín virus and Lassa virus represent important hum... more Among the members of the Arenaviridae family, Junín virus and Lassa virus represent important human health threats generating annual outbreaks of severe human hemorrhagic fever (HF) in endemic areas of Argentina and Western Africa, respectively. Given the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. During the last two decades, academic research studies originated important results identifying novel molecules to be considered for further in vivo characterization. This chapter summarizes experimental in vitro approaches used to determine the possible mechanism of action of these antiviral agents.

This chapter summarizes the main contributions for antiviral development from scientists in Latin... more This chapter summarizes the main contributions for antiviral development from scientists in Latin America in the last decade. Antiviral research in this region has been mainly focused on the search for alternative therapeutic agents for herpes simplex virus infections and the development of antiviral strategies to handle neglected viral diseases that represent a serious threat for local public health. The antiviral potential of natural extracts and compounds isolated from a vast diversity of plants, algae, and other natural sources has also been explored. Similarly, the study of the efficacy and mode of action of a variety of synthetic compounds reveals the ongoing progress for antiviral research in the region. In addition, approaches based on host factors as antiviral targets and the use of bioinformatics methods that allow structure-based design of viral inhibitors have strongly emerged during the last years as powerful tools used by Latin-American researchers for the development ...

Nature Neuroscience, 2020

In the version of this article initially published, two plasmids were listed incorrectly in the M... more In the version of this article initially published, two plasmids were listed incorrectly in the Methods section. Plasmid phDLX1-N174 (#66859) should be #60859, and phDLX2-N174 (#66860) should be 60860. The error has been corrected in the PDF and HTML versions of this article.

European Journal of Medicinal Chemistry, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

International Journal of Infectious Diseases, 2012

Current Medicinal Chemistry, 2013

Acridones are a class of compounds that have attracted attention in recent years for their wide r... more Acridones are a class of compounds that have attracted attention in recent years for their wide range of biological properties, including selective inhibition of diverse human pathogenic viruses. The wide spectrum of antiviral activity includes DNA and RNA viruses, such as herpes simplex virus, cytomegalovirus, adenovirus, hepatitis C virus, dengue virus, and Junin virus, among others, indicative of the involvement of cellular factors as potential targets of acridone derivatives. At the present, their precise mode of action is not clearly determined, although the predominant action seems to be centered on the synthesis of nucleic acids. Regarding this point, inhibitory activity against cellular and viral enzymes and the ability to intercalate into nucleic acid molecules was demonstrated for some acridone compounds. Then, the possibility of a multiple effect on different targets renewed interest in these agents for virus chemotherapy allowing a potent inhibitory effectiveness associated to less feasibility of generating antiviral resistance. This review summarizes the current knowledge regarding the methods of synthesis, the antiviral properties of acridone derivatives, their mechanism of action, and structural characteristics related to antiviral activity as well as the perspectives of this class of compounds for clinical application against human viral infections.

Journal of Cellular Physiology

In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale in Micronesia... more In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale in Micronesia, South Pacific islands, and more recently in the Caribbean and South America. The severity of the clinical presentation in neonates from pregnant women infected with ZIKV during the last outbreak supports the relevance of unraveling the mechanism of infection and viral persistence in the placenta with local viral isolates. Here, we investigated the relevance of trophoblast metabolic rewiring for viral multiplication and the role of the vasoactive intestinal peptide (VIP) as an endogenous factor associated with placental restriction to ZIKV infection at early pregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring in first trimester cytotrophoblast‐derived cells by increasing glucose utilization as fuel to sustain its replication, decreasing long‐chain polyunsaturated fatty acid uptake, and promoting lipid droplets accumulation to favor its multiplication. Of not...

Molecules, 2020

Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoro... more Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3′-(difluoromethyl)-4′-methoxycinnamoyl amides using Deoxofluor® as a fluorinating agent. The N-isopropyl, N-isopentyl, and N-(2-phenylethyl) amides 11b, 11d and 11g were the most active and selective against Mycobacterium smegmatis (MIC = 8 µg/mL) with 11b and 11g displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of N-isopropylamide 11b were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards M. smegmatis, changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards M....

Los dominios zinc fingers son elementos estructurales muy estables cuya particularidad es la coor... more Los dominios zinc fingers son elementos estructurales muy estables cuya particularidad es la coordinación de uno o más átomos de zinc a través de residuos de cisteínas e histidinas. Los zinc fingers son uno de los motivos más encontrados en las proteínas, y esto es de gran relevancia ya que por medio de los mismos participan en interacciones específicas con distintas macromoléculas (proteínas y ácidos nucleicos). Teniendo en cuenta las características de estas estructuras, y la variedad de funciones que cumplen, muchos grupos de investigación se dedican hoy a utilizar estos motivos para estudiar interacciones entre macromoléculas o como herramientas en biología molecular.

Antiviral chemistry & chemotherapy, 2008

In the present study, a series of N-substituted acridone derivatives was synthesized and evaluate... more In the present study, a series of N-substituted acridone derivatives was synthesized and evaluated against two haemorrhagic fever viruses (HFV). Compounds were tested against Junin virus (JUNV), an arenavirus agent of Argentine haemorrhagic fever, and dengue virus (DENV), a flavivirus agent of the most prevalent arthropod-borne viral disease in humans. Among tested compounds, two N-allyl acridones (derivatives 3c and 3f) elicited a potent and selective antiviral activity against JUNV (strain 1V4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 microM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 microM, resulting in selectivity indices >181.8-400.0. Both acridones were effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment, indica...

Antiviral Research, 2011

Arenaviruses such as Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are b... more Arenaviruses such as Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are benign in their natural reservoir hosts, and can occasionally cause severe viral hemorrhagic fever (VHF) in non-human primates and in human beings. LCMV is considerably more benign for human beings than Lassa virus, however certain strains, like the LCMV-WE strain, can cause severe disease when the virus is delivered as a high-dose inoculum. Here we describe a rhesus macaque model for Lassa fever that employs a virulent strain of LCMV. Since LASV must be studied within Biosafety Level-4 (BSL-4) facilities, the LCMV-infected macaque model has the advantage that it can be used at BSL-3. LCMV-induced disease is rarely as severe as other VHF, but it is similar in cases where vascular leakage leads to lethal systemic failure. The LCMVinfected macaque has been valuable for describing the course of disease with differing viral strains, doses and routes of infection. By monitoring system-wide changes in physiology and gene expression in a controlled experimental setting, it is possible to identify events that are pathognomonic for developing VHF and potential treatment targets.

Antiviral Chemistry and Chemotherapy, 2000

Fifteen antiretroviral Zn-finger active compounds with diverse chemical structures, including azo... more Fifteen antiretroviral Zn-finger active compounds with diverse chemical structures, including azoic compounds, hydrazide derivatives, disulphide-based reagents and others were screened in vitro against Junin virus (JUNV), the aetiological agent of Argentine haemorrhagic fever, by a virus yield inhibition assay in Vero cells. Cytotoxicity was evaluated simultaneously by the MTT method. Of the compounds, three were totally inactive as antivirals, nine presented moderate anti JUNV-activity and three were truly active with EC50 (effective concentration 50%) values in the range 6.5–9.3 μM and with selectivity indices greater than 10. The most active inhibitors, named NSC20625, 3–7 and 2–71, demonstrated a broad range of action against arenaviruses, including several attenuated and pathogenic strains of JUNV as well as the antigenically related Tacaribe virus (TACV) and Pichinde virus (PICV). The direct treatment of JUNV and TACV virions with the compounds showed two types of behaviour: t...