ArticlePloS one2017
Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 36 citations in OpenAlex.
- Kinesin light chain 1 interacts with NS1 and is a susceptibility factor for dengue virus infection in mosquito cells.The Journal of general virology · 2025Article
- Lipid Droplets: Formation, Degradation, and Their Role in Cellular Responses to Flavivirus Infections.Microorganisms · 2024Review
- Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.iScience · 2024Article
- The proprotein convertase SKI-1/S1P is a critical host factor for Nairobi sheep disease virus infectivity.Virus research · 2023Article
- Lipid droplets in Zika neuroinfection: Potential targets for intervention?Memorias do Instituto Oswaldo Cruz · 2023Review
- Lipid Droplets and Their Participation in Zika Virus Infection.International journal of molecular sciences · 2022Review
- Subtilisin ofCurrent issues in molecular biology · 2022Article
- Article
- How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?Viruses · 2021Review
- Manipulation of Host Cell Organelles by Intracellular Pathogens.International journal of molecular sciences · 2021Review
- Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions.Frontiers in cell and developmental biology · 2021Review
- PF-429242, a Subtilisin Inhibitor, Is EffectiveFrontiers in microbiology · 2021Article
- Molecular Events Occurring in Lipophagy and Its Regulation inFrontiers in microbiology · 2021Review
- Hijacking of Lipid Droplets by Hepatitis C, Dengue and Zika Viruses-From Viral Protein Moonlighting to Extracellular Release.International journal of molecular sciences · 2020Review
- Contemporary Strategies and Current Trends in Designing Antiviral Drugs against Dengue Fever via Targeting Host-Based Approaches.Microorganisms · 2019Review
- Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies.Frontiers in cell and developmental biology · 2019Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Viral hijacking and manipulation of host-cell biosynthetic pathways by human enveloped viruses are shared molecular events essential for the viral lifecycle. For Flaviviridae members such as hepatitis C virus and dengue virus (DENV), one of the key subsets of cellular pathways that undergo manipulation is the lipid metabolic pathways, underlining the importance of cellular lipids and, in particular, lipid droplets (LDs) in viral infection. Here, we hypothesize that targeting cellular enzymes that act as key regulators of lipid homeostasis and LD formation could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with all DENV serotypes (1-4) circulating around the world. Using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrate that inhibition of SKI-1/S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the LD numbers and LD-positive areas and provides a means of effectively inhibiting infection by DENV (1-4). Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV infection [median inhibitory dose (EC50) = 1.2 microM; median cytotoxic dose (CC50) = 81 microM; selectivity index (SI) = 68)] and a ~3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid, which acts as an inducer of LD formation in PF-429242-treated and non-treated control cells. Collectively, our results demonstrate that human SKI-1/S1P is a potential target for indirect-acting pan-serotypic anti-DENV agents and reveal new therapeutic opportunities associated with the use of lipid-modulating drugs for controlling DENV infection.
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