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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Daniela Carbone - , University of Palermo (Erstautor:in)
  • Mark F. Santos - , Touro University - Nevada (Erstautor:in)
  • Denis Corbeil - , Forschungsgruppe Tissue Engineering, Gewebe Engineering (FoG) (Autor:in)
  • Giulio Vistoli - , Università degli Studi di Milano (Autor:in)
  • Barbara Parrino - , University of Palermo (Autor:in)
  • Jana Karbanova - , Forschungsgruppe Tissue Engineering, Gewebe Engineering (FoG) (Autor:in)
  • Stella Cascioferro - , University of Palermo (Autor:in)
  • Camilla Pecoraro - , University of Palermo (Autor:in)
  • Jodi Bauson - , Touro University - Nevada (Autor:in)
  • Waleed Eliwat - , Touro University - Nevada (Autor:in)
  • Feryal Aalam - , Touro University - Nevada (Autor:in)
  • Girolamo Cirrincione - , University of Palermo (Autor:in)
  • Aurelio Lorico - , Touro University - Nevada (Autor:in)
  • Patrizia Diana - , University of Palermo (Autor:in)

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.

Details

OriginalspracheEnglisch
Aufsatznummer107589
Seiten (von - bis)1-15
Seitenumfang15
FachzeitschriftBioorganic chemistry : an international journal
Jahrgang150
PublikationsstatusVeröffentlicht - Sept. 2024
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0003-1181-3659/work/162845586
ORCID /0000-0001-7687-0983/work/162845781
Mendeley 5c5542f7-3eac-3faa-a57d-d0212d96ec6c
Scopus 85196962936

Schlagworte

Schlagwörter

  • Anti-cancer, Anti-HIV-1, exosomes, VOR complex, microvesicles, Itraconazole derivative, Exosome, Microvesicle

Bibliotheksschlagworte