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      • Record: found
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      A new host-targeted antiviral cyclolignan (SAU-22.107) for Dengue Virus infection in cell cultures. Potential action mechanisms based on cell imaging ☆

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Highlights

          • •

            Dengue virus (DENV) infection is the most arbovirosis in the world.

          • •

            medications have not been approved for DENV treatment.

          • •

            Drug discovery based on the host-targeted antiviral (HTA) constitutes a new promising strategy, considering the high genetic barrier to resistance of DENV.

          • •

            A new host-targeted antiviral cyclolignan (S.71) decreases the viral yield through an HTA-related mechanism of action, possibly altering the DENV genome replication and/or polyprotein translation, through the alteration of microtubule distribution and endoplasmic reticulum deterioration.

          Abstract

          Dengue virus (DENV) infection is the most arbovirosis in the world. However, medications have not been approved for its treatment. Drug discovery based on the host-targeted antiviral (HTA) constitutes a new promising strategy, considering their high genetic barrier to resistance and the low probability of selecting drug resistance strains. In this study, we have tested fifty-seven podophyllotoxin-related cyclolignans on DENV-2 infected cells and found the most promising compound was S.71. Using cellular and molecular biology experiments, we have discovered that the new lignan altered the distribution of microtubules, induced changes in cell morphology, and caused retraction of the rough endoplasmic reticulum. In addition, the compound alters the viral envelope protein and the double-stranded RNA, while there is a decrease in negative-strand RNA synthesis; especially when the compound was added between 6- and 12-hours post-infection. Altogether, S.71 decreases the viral yield through an HTA-related mechanism of action, possibly altering the DENV genome replication and/or polyprotein translation, through the alteration of microtubule distribution and endoplasmic reticulum deterioration. Finally, pharmacokinetic predictors show that S.71 falls within the standard ranges established for drugs.

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          Most cited references50

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          Apoptosis: a review of programmed cell death.

          Susan A. Elmore (2007)
          The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
          Article 0 comments Cited 1857 times – based on 0 reviews     Review now
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            Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.

            Richard Friesner, Jay L. Banks, Robert B Murphy … (2004)
            Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
            Article 0 comments Cited 1114 times – based on 0 reviews     Review now
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              Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.

              Richard Friesner, Robert B Murphy, Matthew Repasky … (2006)
              A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
              Article 0 comments Cited 925 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                José Luis López-Pérez
                Juan Carlos Gallego-Gómez
                Journal
                Journal ID (nlm-ta): Virus Res
                Journal ID (iso-abbrev): Virus Res
                Title: Virus Research
                Publisher: Elsevier
                ISSN (Print): 0168-1702
                ISSN (Electronic): 1872-7492
                Publication date PMC-release: 04 November 2022
                Publication date Collection: 02 January 2023
                Publication date (Electronic): 04 November 2022
                Volume: 323
                Electronic Location Identifier: 198995
                Affiliations
                [a ]Group of Investigative Dermatology, Institute of Medical Research, Faculty of Medicine, University of Antioquia, Medellin, Colombia
                [b ]Translational and Molecular Medicine Group, Institute of Medical Research, Medicine Faculty, University of Antioquia, Medellin, Colombia
                [c ]Departamento de Ciencias Farmacéuticas, Área de Química Farmacéutica, Facultad de Farmacia, CIETUS, IBSAL. Campus Miguel de Unamuno, University of Salamanca, 37007, Salamanca, Spain
                [d ]Facultad de Medicina, Universidad de Panamá, Panamá, R. de Panamá
                [e ]Programa de Pós-graduação em Ciências Farmacéuticas, Universidade do Vale do Itajaí, UNIVALI, Itajaí, SC, Brazil
                Author notes
                Article
                Publisher Item ID: S0168-1702(22)00324-0 Publisher ID: 198995
                DOI: 10.1016/j.virusres.2022.198995
                PMC ID: 10194330
                PubMed ID: 36336130
                SO-VID: 3c770c16-4971-4f11-8f91-b05949261f84
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 6 July 2022
                Date revision received : 31 October 2022
                Date accepted : 31 October 2022
                Categories
                Subject: Article

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: dengue,host-targeted antiviral,cytotoxicity,microtubule,endoplasmic reticulum, and cyclolignan
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: dengue, host-targeted antiviral, cytotoxicity, microtubule, endoplasmic reticulum, and cyclolignan

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