LEDGINs, Inhibitors of the Interaction Between HIV-1 Integrase and LEDGF/p75, Are Potent Antivirals with a Potential to Cure HIV Infection

Debyser, Zeger; Bruggemans, Anne; Belle, Siska Van; Janssens, Julie; Christ, Frauke

doi:10.1007/978-981-16-0267-2_4

Cited by 7 publications

(3 citation statements)

References 123 publications

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“…Further, our observation that the sensitivity to DTX in chemoresistant PCa cells was significantly augmented when EXI and RELA were used in combination with LEDGF/p75 silencing suggests that combining LEDGF/p75 inhibitors with these SMGRs could be an effective therapeutic strategy to increase prostate tumor response to taxanes. Ongoing efforts in the discovery of small molecule inhibitors targeting the HIV integrase–LEDGF/p75 interaction [ 114 , 115 ] may potentially yield LEDGF/p75 inhibitors that could be repurposed for the treatment of advanced PCa in combination with SMGRs and taxanes.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Sanchez-Hernández

Ochoa

Suzuki

et al. 2023

Cells

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Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Sanchez-Hernández

Ochoa

Suzuki

et al. 2023

Cells

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“…Several small molecules have been identified as inhibitors of the IN-LEDGF/p75 interaction, including KF116, MUT-A, BI224436, CX14442, BI-D, LEDGIN 1, et al. [ 26 , 27 ]. Flavonoids, as plant metabolites, have been shown to block the enzymatic activity of IN and IN-LEDGF/p75 interaction [ 16 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a flavonoid library for inhibition of interaction of HIV-1 integrase with human LEDGF/p75 towards a structure–activity relationship

et al. 2022

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Background: Proteinśprotein interaction (PPI) between lens epithelium-derived growth factor (LEDGF/p75) and human immunodeficiency virus (HIV) integrase (IN) becomes an attractive target for anti-HIV drug development. Methods: The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. In this study, a panel of 99 structurally related flavonoids were was tested, concerning their ability to inhibit IN-LEDGF/p75 interaction, using a homogeneous time time-resolved fluorescence (HTRF) assay. Results: From the obtained results, it was possible to observe that the flavonoid with hydroxyl group in C3-, C4-, C5- and C7-position on the A-ring, C4′- and C5′-position of the B-ring, a carbonyl group of the C-ring, was more active against IN-LEDGF/p75 interaction, through competitive inhibition. Moreover, the binding modes of representative compounds, including myricetin, luteolin, dihydrorobinetin, naringenin, epicatechin, genistein and helichrysetin, were analyzedanalysed by molecular docking. Biolayer interferometry assay confirmed that these representative compounds disrupted the PPI by binding to IN with KD values ranging from 1.0 to 3.6 µM. Conclusion: This study presents the first to quantitative comparation of the effect of flavonoids with different structural subclasses on IN-LEDGF/p75 interaction. Our findings provide new insights into the development of inhibitors targeting IN-LEDGF/p75 interaction using flavonoids. Key Messages HIV-1 integrase (IN)-LEDGF/p75 interaction is an attractive target for antiviral drug development. For the first time, the structure-activity relationship of flavonoids belonging to seven flavonoidic subclasses on IN-LEDGF/p75 interaction was determined. This study comprehends an HTRF-based screening system, biolayer interferometry and an in silico molecular docking analysis.

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“…Despite successful antiretroviral therapy (ART), strongly limiting HIV-1 transmission, the persistence of a long-term proviral reservoir frustrates efforts to achieve a cure. Thus, a strong need to understand host–HIV-1 interactions, particularly the mechanisms underlying viral DNA integration into the human genome is crucial to identify therapeutic and potentially curative targets ( 1 , 2 ).…”

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confidence: 99%

Integrase-LEDGF/p75 complex triggers the formation of biomolecular condensates that modulate HIV-1 integration efficiency in vitro

Batisse,

Lapaillerie,

Humbert

et al. 2024

Journal of Biological Chemistry

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LEDGINs, Inhibitors of the Interaction Between HIV-1 Integrase and LEDGF/p75, Are Potent Antivirals with a Potential to Cure HIV Infection

Cited by 7 publications

References 123 publications

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Evaluation of a flavonoid library for inhibition of interaction of HIV-1 integrase with human LEDGF/p75 towards a structure–activity relationship

Integrase-LEDGF/p75 complex triggers the formation of biomolecular condensates that modulate HIV-1 integration efficiency in vitro

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