2. Academic Validation
  3. Triazole derivatives inhibit the VOR complex-mediated nuclear transport of extracellular particles: Potential application in cancer and HIV-1 infection

Triazole derivatives inhibit the VOR complex-mediated nuclear transport of extracellular particles: Potential application in cancer and HIV-1 infection

  • Bioorg Chem. 2024 Sep:150:107589. doi: 10.1016/j.bioorg.2024.107589.
Daniela Carbone 1,  Mark F Santos 2,  Denis Corbeil 3,  Giulio Vistoli 4,  Barbara Parrino 5,  Jana Karbanová 6,  Stella Cascioferro 7,  Camilla Pecoraro 8,  Jodi Bauson 9,  Waleed Eliwat 10,  Feryal Aalam 11,  Girolamo Cirrincione 12,  Aurelio Lorico 13,  Patrizia Diana 14
Affiliations

Affiliations

  • 1 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: daniela.carbone@unipa.it.
  • 2 Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA. Electronic address: msantos17@touro.edu.
  • 3 Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany; Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany. Electronic address: denis.corbeil@tu-dresden.de.
  • 4 Department of Pharmaceutical Sciences, University of Milan, Milan, Italy. Electronic address: giulio.vistoli@unimi.it.
  • 5 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: barbara.parrino@unipa.it.
  • 6 Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany; Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany. Electronic address: jana.karbanova@tu-dresden.de.
  • 7 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: stellamaria.cascioferro@unipa.it.
  • 8 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: camilla.pecoraro@unipa.it.
  • 9 Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA. Electronic address: Jbauson@student.touro.edu.
  • 10 Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA. Electronic address: weliwat@student.touro.edu.
  • 11 Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA. Electronic address: farizeh.aalam@gmail.com.
  • 12 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: girolamo.cirrincione@unipa.it.
  • 13 Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA. Electronic address: alorico@touro.edu.
  • 14 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy. Electronic address: patrizia.diana@unipa.it.
PMID: 38941696 DOI: 10.1016/j.bioorg.2024.107589
Abstract

Extracellular vesicles (EVs) appear to play an important role in intercellular communication in various physiological processes and pathological conditions such as Cancer. Like enveloped viruses, EVs can transport their contents into the nucleus of recipient cells, and a new intracellular pathway has been described to explain the nuclear shuttling of EV cargoes. It involves a tripartite protein complex consisting of vesicle-associated membrane protein-associated protein A (VAP-A), oxysterol-binding protein (OSBP)-related protein-3 (ORP3) and late endosome-associated Rab7 allowing late endosome entry into the nucleoplasmic reticulum. Rab7 binding to ORP3-VAP-A complex can be blocked by the FDA-approved Antifungal drug itraconazole. Here, we design a new series of smaller triazole derivatives, which lack the dioxolane moiety responsible for the Antifungal function, acting on the hydrophobic sterol-binding pocket of ORP3 and evaluate their structure-activity relationship through inhibition of VOR interactions and nuclear transfer of EV and HIV-1 cargoes. Our investigation reveals that the most effective compounds that prevent nuclear transfer of EV cargo and productive Infection by VSV-G-pseudotyped HIV-1 are those with a side chain between 1 and 4 carbons, linear or branched (methyl) on the triazolone region. These potent chemical drugs could find clinical applications either for nuclear transfer of cancer-derived EVs that impact metastasis or viral Infection.

Keywords

Anti-HIV-1; Anti-cancer; Exosome; Itraconazole derivative; Microvesicle; VOR complex.

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