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Molecules ; 27(3)2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-35164343

RESUMO

Since the efficiency in the transcription of the HIV genome contributes to the success of viral replication and infectivity, we investigated the downregulating effects of the spirobisindole alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) from the endemic Philippine medicinal plant, Voacanga globosa, during HIV gene transcription. Alkaloids 1-3 were explored for their inhibitory activity on TNF-α-induced viral replication in two latently HIV-infected cell lines, OM10.1 and J-Lat. The induction of HIV replication from OM10.1 and J-Lat cells elicited by TNF-α was blocked by globospiramine (1) within noncytotoxic concentrations. Furthermore, globospiramine (1) was found to target the NF-ĸB activation cascade in a dose-dependent manner when the transcriptional step at which inhibitory activity is exerted was examined in TNF-α-induced 293 human cells using transient reporter (luciferase) gene expression systems (HIV LTR-luc, ĸB-luc, and mutant ĸB-luc). Interrogation through molecular docking against the NF-ĸB p50/p65 heterodimer and target sites of the subunits comprising the IKK complex revealed high binding affinities of globospiramine (1) against the S281 pocket of the p65 subunit (BE = -9.2 kcal/mol) and the IKKα activation loop (BE = -9.1 kcal/mol). These findings suggest globospiramine (1) as a molecular inspiration to discover new alkaloid-based anti-HIV derivatives.


Assuntos
Alcaloides/farmacologia , Infecções por HIV/metabolismo , HIV-1/fisiologia , Quinase I-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Voacanga/química , Alcaloides/química , Linhagem Celular , Relação Dose-Resposta a Droga , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Células HL-60 , Humanos , Quinase I-kappa B/química , Alcaloides Indólicos/farmacologia , Modelos Biológicos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/química , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fator de Transcrição RelA/química , Fator de Necrose Tumoral alfa/farmacologia , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
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