Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro

Lü, Jianming; Yan, Shaoyu; Jamaluddin, Saha; Weakley, Sarah M.; Liang, Zhibin; Siwak, Edward B.; Yao, Qizhi; Chen, Changyi

doi:10.12659/msm.883261

Cited by 49 publications

(41 citation statements)

References 17 publications

(18 reference statements)

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“…The Ginkgolic acids C13:0, C15:1 and C17:1 are commercially available compounds of Ginkgo leaves. The antioxidative activity of GA has been reported to have multiple therapeutic effects including the treatment of cardiovascular disease, HIV infection, bacterial infections such as Escherichia coli and Staphylococcus aureus, and some tumors 7,8,19,20 . It has been suggested that GA may operate by several other pathways including: inhibition of fatty acid synthase 10 ; non-specific SIRT inhibition 11 ; activation of protein phosphatase type-2C 12 ; suppression of STAT3 activation through induction of PTEN and SHP-1 Tyrosine Phosphatase 21 , and protection against Aβ-induced synaptic dysfunction in the hippocampus 6 .…”

Section: Discussionmentioning

confidence: 99%

Ginkgolic acid inhibits fusion of enveloped viruses

Borenstein

Hanson

Markosyan

et al. 2020

Sci Rep

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Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-β (Aβ) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus.Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).Ginkgolic acids are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. Ginkgo biloba extracts (GBE) have been used as herbal supplements since at least the 16 th century and remain widely in use 1 . Major constituents of GBE include terpine trilactones (ginkgolide A, B, C, J, and bilobalide), flavonoid glycosides (quercetin and rutin), as well as Ginkgolic acids 2 . Ginkgolic acids are a mixture of several 2-hydroxy-6-alkylbenzoic acids in which the most common alkyl chains contain 13, 15, or 17 carbons. The 15 and 17 carbon chains are unsaturated at positions 8 and 10, respectively. The 3 Ginkgolic acid (GA) structures are, therefore, designated C13:0, C15:1, and C17:1 (Table S1) 3 .GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; potential rescue of amyloid-β (Aβ) induced synaptic impairment; and inhibition of HIV protease activity as well as HIV viral replication 4-7 . GA was also reported to have activity against Escherichia coli and Staphylococcus aureus 8 . Several ways in which GA works have been suggested including by SUMOylation inhibition activity; blocking formation of the E1-SUMO intermediate 9 ;...

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Section: Discussionmentioning

confidence: 99%

Ginkgolic acid inhibits fusion of enveloped viruses

Borenstein

Hanson

Markosyan

et al. 2020

Sci Rep

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“…Another possible mechanism might rely on the Bcl-2/Bax pathway, which contributes to the antitumoral and anti-HIV effects of GA (Wang H. et al, 2010; Zhou et al, 2010; Lü et al, 2012). Inasmuch, as Bcl-2/Bax is also involved in Aβ-mediated impairment of LTP (Olsen and Sheng, 2012), it can be hypothesized that the protective effect of GA here observed might be mediated by Bcl-2/Bax inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, GA is able to induce neuronal death at high concentrations (Ahlemeyer et al, 2001); accordingly, today all commercial preparations of Ginkgo leaf contain low dose of GA in order to minimize side effects (McKenna et al, 2001). However, there is recent evidence that GA has different protective effects, as well as antitumoral and anti-HIV effects (Wang H. et al, 2010; Zhou et al, 2010; Lü et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Ginkgolic Acid Protects against Aβ-Induced Synaptic Dysfunction in the Hippocampus

2016

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Ginkgo leaf is the most used form of supplement for cognitive ailments. The standardized extract formulation EGb 761 is a dietary supplement with proven benefit in several neurological and psychiatric conditions including memory decline in Alzheimer’s disease, schizophrenia and dementia. Ginkgolic acid (GA) is a component of this extract which shows pleiotropic effects including antitumoral and anti-HIV action; however, its effect on memory is still unknown. Here, we carried out an electrophysiological analysis to investigate the effects of GA on long term potentiation and synaptic transmission at CA1 hippocampal synapses. We also evaluated the potential rescuing effect of GA on the synaptic dysfunction following in vitro application of Aβ. Data obtained indicate that GA exerts neuroprotective effects against Aβ-induced impairment of neurotransmitter release and synaptic plasticity.

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“…GA, which is characterized by a mixture of components containing 13-19 side chain carbon atoms at site 6 and 0-3 side chain double bonds, can be extracted from ginkgo fruit, exotesta and leaves (8)(9)(10). GA has been reported to display a wide range of bioactive properties, including antimicrobial, antivirus and molluscicidal activities (11). Accumulating evidence has demonstrated that several monomer structures of GA (C13:0, C15:0 and C17:1) exert antitumor activity in a number of human malignancies, including hepatocellular carcinoma as well as colon, breast and lung cancer (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Ginkgolic acid inhibits the growth of renal cell carcinoma cells via inactivation of the EGFR signaling pathway

Zhu

Na²,

Huang³

et al. 2020

Exp Ther Med

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Renal cell carcinoma (RCC) is one of the most common urological malignancies occurring in adult human kidneys worldwide. Recent research on antitumor drugs has focused on plant extracts, a class of compounds that play critical roles in cancer treatment. The present study aimed to investigate the potential antitumor effect of ginkgolic acid (GA) in RCC. Transwell invasion assay, cell counting kit-8 assay and flow cytometry were used to measure cell migration, cell viability and apoptosis, respectively. A network pharmacology approach was applied to identify pathway information, combining molecular docking techniques to screen for key target information. In the present study, GA inhibited the viability and proliferation of RCC cells (786-O and A498), both in vitro and in vivo, via G 1 arrest. GA also reduced RCC cell invasion and migration. In addition, the epidermal growth factor receptor (EGFR) was identified as a critical target protein of GA, which significantly inactivated EGFR signaling in RCC (P<0.05). Collectively, the present study provided evidence that GA exerts its anticancer function by directly targeting the EGFR signaling pathway, revealing the potential of GA therapy for RCC.

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Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro

Cited by 49 publications

References 17 publications

Ginkgolic acid inhibits fusion of enveloped viruses

Ginkgolic acid inhibits fusion of enveloped viruses

Ginkgolic Acid Protects against Aβ-Induced Synaptic Dysfunction in the Hippocampus

Ginkgolic acid inhibits the growth of renal cell carcinoma cells via inactivation of the EGFR signaling pathway

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