Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

Jonathan E Buckendorf,Norbert Kúsz,Peter Waweru Mwangi,Judit Hohmann,Adam M Spivak,Racheal A Nell,Róbert Berkecz,Yu-Chi Tsai,Dóra Rédei,Andrea Vasas

doi:10.3390/ph14070653

Jonathan E Buckendorf, Norbert Kúsz + Show 8 more

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https://doi.org/10.3390/ph14070653

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Abstract

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (1–9, 14–17, 19, and 20) along with 16 known compounds from E. usambarica with HIV-1 latency reversal activity. Euphordraculoate C (1) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (2) and B (3) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4β-Crotignoid K (14) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (13), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids 12–14 and 21 for the HIV-1 latency reversal activity was activation of PKC, while lignans 26 and 27 that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from E. usambarica have the potential to contribute to the development of HIV-1 eradication strategies.

Highlights

Antiretroviral therapy (ART) durably blocks HIV-1 transcription by targeting viral enzymes; these drugs do not result in viral eradication due to the presence of replication-competent proviruses that are stably integrated into the genomes of a small population of long-lived memory T cells, known as the latent reservoir [1]
The partitioned n-hexane (EU-H) and dichloromethane (EU-C) phases significantly improved upon reactivation efficacy compared to the EU
Usambariphanes A (2) and B (3) displayed an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure, which is different from such lactone ring commonly constructed between C-17 and C-3 or between C-17 and C-5

Summary

Introduction

Antiretroviral therapy (ART) durably blocks HIV-1 transcription by targeting viral enzymes; these drugs do not result in viral eradication due to the presence of replication-competent proviruses that are stably integrated into the genomes of a small population of long-lived memory T cells, known as the latent reservoir [1]. A promising strategy to address HIV-1 persistence is to use small molecules to reactivate latent proviruses in order to expose these cells to immune clearance and/or viral cytopathic effect. The Euphorbia is one of the largest genera in Euphorbiaceae [5,6]. There are many bioactive secondary metabolites in the genus Euphorbia, including more than 20 different types of diterpenoids (abietane, atisane, casbane, daphnane, ingenane, jatrophane, karane, lathyrane, tigliane, and others) [7]. Sesquiterpenoids, triterpenoids, flavonoids, alkaloids, polyphenols, tannins, volatile compounds, and phytosterols have

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