title: 1-Cinnamoyl-3,11-dihydroxymeliacarpin delays glycoprotein transport restraining virus multiplication without cytotoxicity.
abstract: The 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), isolated from extracts of Melia azedarach L., displays antiviral and immunomodulating properties. CDM is the first reported tetranortriterpenoid responsible for the alkalinization of intracellular compartments affecting both, viral endocytic and exocytic pathways. Considering that viral glycoprotein synthesis is completely dependent upon cellular membrane trafficking, we questioned whether CDM might also interfere with the normal transport of cellular glycoproteins. This study demonstrates that CDM promoted a transient block in the transport of two cellular glycoproteins, the transferrin receptor (TfR) and TNF-alpha. Nevertheless, CDM did not affect the transferrin binding ability of TfR and did not impede the TNF-alpha secretion. On the other hand, CDM disturbed the intracellular localization of capsid, glycoprotein and tegument proteins simultaneously in the same HSV-1 infected cells. Besides, we show that concanamycin A and monensin provoke a permanent blockage of viral and cellular glycoproteins, in contrast to the delay observed after CDM treatment. Thus, the delay on glycoprotein transport caused by CDM would account for the strong inhibition on virus multiplication without interfering with the bioactivity of cellular glycoproteins.
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, FCEN, UBA, Pabellón II- Piso 4to, Ciudad Universitaria, C-1428BGA, Buenos Aires, Argentina.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bueno
authors.forename: Laura E
authors.initials: LE
authors.lastname: Alché
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Barquero
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D006023:Glycoproteins / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D036701:Limonins / Q000009:adverse effects / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D031586:Melia azedarach / Q000737:chemistry; D008985:Monensin / Q000494:pharmacology; D021381:Protein Transport; D011990:Receptors, Transferrin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C474472:1-cinnamoyl-3,11-dihydroxymeliacarpin; D000998:Antiviral Agents; D006023:Glycoproteins; D036701:Limonins; D018942:Macrolides; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; C515577:glycoprotein gD, herpes simplex virus type 1; C036978:concanamycin A; D008985:Monensin