Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-kB Cascade: In Vitro and In Silico Investigations.

Ma De Jesus,Von De Leon,Takashi Okamoto,John Ramos,Kaori Asamitsu,Allan Macabeo

doi:10.3390/molecules27031078

Ma De Jesus, Von De Leon + Show 4 more

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https://doi.org/10.3390/molecules27031078

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Abstract

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.

Highlights

Introduction published maps and institutional affilInfection by human immunodeficiency virus (HIV) displays a spectrum of signs and symptoms that escalates to damage the immune system, leading to Acquired ImmuneDeficiency Syndrome (AIDS)
We explored the in vitro anti-HIV activity of three spirocyclic bisindole alkaloids from Voacanga globosa (Merr.) Blanco, namely globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3), by screening the inhibitory activity of viral transcription utilizing human cell lines latently infected with HIV, namely
Natural products have been desired as HIV therapeutic inspirations, because they are generally safe and accessible for isolation and synthesis

Summary

Introduction

Introduction published maps and institutional affilInfection by human immunodeficiency virus (HIV) displays a spectrum of signs and symptoms that escalates to damage the immune system, leading to Acquired ImmuneDeficiency Syndrome (AIDS). Around 37.9 million people are living with HIV (PLHIV), 23.3 million of which received antiretroviral therapy (ART) at the end of 2020 [1]. In the Philippines, where there is an alarming increase in HIV infections, cumulative data from 1984 to August 2021 showed 53,286 PLHIV are on ART [2]. The current antiretroviral drugs target viral enzymes, including reverse transcriptase, integrase, and protease, and it is carried out usually in combination [3,4], which has been generally effective in treating HIV infections with a low likelihood of progressing to AIDS [5]. High morbidity and mortality rates still outpace the treatment response on a global scale because of (1) limited accessibility to antiretroviral drugs, often limited to average- to high-income countries [6],.

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