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Sesterterpenoids Isolated from the Sponge Phorbas sp. Activate Latent HIV-1 Provirus Expression
Meng Wang1, Ian Tietjen2, Min Chen1
1Departments of Chemistry and Earth, Oceans & Atmospheric Sciences, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1.
The Journal of Organic Chemistry
|November 5, 2016
Summary
Marine sponge Phorbas sp. yielded eight new sesterterpenoids. Some compounds, like alotaketal C, show potential for reversing latent human immunodeficiency virus (HIV) infection by activating protein kinase C signaling.
Area of Science:
- Marine Natural Products Chemistry
- Chemical Biology
- Organic Chemistry
Background:
- Marine sponges are a rich source of structurally diverse secondary metabolites.
- Sesterterpenoids, a class of C20 terpenoids, exhibit a wide range of biological activities.
- Latent human immunodeficiency virus (HIV) infection remains a significant challenge for eradication therapies.
Purpose of the Study:
- To isolate and characterize novel sesterterpenoids from the marine sponge Phorbas sp.
- To investigate the potential of these compounds as latency reversal agents for HIV-1.
- To elucidate the structure-activity relationships of sesterterpenoids in modulating HIV proviral gene expression.
Main Methods:
- Isolation and purification of sesterterpenoids using chromatographic techniques.
- Structure elucidation employing Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) data analysis.
- Assessment of latency reversal activity using a cell culture model of latent HIV-1 infection and protein kinase C signaling assays.
Main Results:
- Eight new sesterterpenoids were identified: alotaketals D-E, ansellones D-G, and anvilones A-B.
- Ansellone F possesses a rare 1,2-3,4-bis-epoxydecalin substructure.
- Anvilones A-B feature an unprecedented tetracyclic anvilane terpenoid carbon skeleton.
- Ansellone A, alotaketal D, and anvilone A demonstrated the ability to induce HIV proviral gene expression.
- The known compound alotaketal C was found to be more potent than the control prostratin in inducing HIV gene expression.
- All identified Phorbas sesterterpenoids with latency reversal properties activated protein kinase C signaling, similar to prostratin.
Conclusions:
- The marine sponge Phorbas sp. is a prolific source of novel sesterterpenoids with unique chemical architectures.
- Several isolated sesterterpenoids, particularly alotaketal C, exhibit promising latency reversal activity against HIV-1.
- The mechanism of action for these compounds involves the activation of protein kinase C signaling pathways.
- These findings highlight the potential of marine natural products as leads for developing new therapeutic strategies against latent HIV infection.
