Isoform-Selective Versus Nonselective Histone Deacetylase Inhibitors in HIV Latency Reversal

Boateng, Anthony Twumasi; Abaidoo-Myles, Araba; Bonney, Evelyn Yayra; Kyei, George B.

doi:10.1089/aid.2021.0195

Cited by 7 publications

(3 citation statements)

References 65 publications

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“…Nonselective pan-HDACi, such as vorinostat and panobinostat, which inhibit many HDAC class isoforms, have a greater potential for toxicity. More selective HDACi that specifically target class I HDACs, like entinostat and romidepsin, may be able to act as LRAs with reduced off-target effects, provided they can exhibit the same potency as the pan-HDACi [143]. In the last decade, four different HDACi were approved by the US-FDA for the treatment of several cancers, and three of these, romidepsin, panobinostat, and vorinostat, have been tested as LRAs in clinical trials (NCT02850016, NCT01680094, NCT01365065, NCT02513901, NCT00289952, NCT01933594, NCT01319383).…”

Section: Histone Deacetylase Inhibitors (Hdaci)mentioning

confidence: 99%

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Duggan,

Dragic,

Chanda

et al. 2023

Viruses

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Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells (“block and lock”) or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host (“shock and kill”). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir.

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Section: Histone Deacetylase Inhibitors (Hdaci)mentioning

confidence: 99%

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Duggan,

Dragic,

Chanda

et al. 2023

Viruses

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“…Specific HDAC isoforms were discovered to be related to definite diseases, such as neurodegenerative disorders and malignancies. Selective HDACis are highly required to understand various HDAC isoforms' biological functions better and, more crucially, for developing medicines with more valuable therapeutic index and fewer adverse effects than pan-inhibitors [20,21].…”

Section: Selective Hdacismentioning

confidence: 99%

Recent review on selective histone deacetylase inhibitors in cancer therapy

Abd El-hameed,

Mohamed,

Beshr

2023

Octahedron Drug Research

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Cancer is the most serious disease afflicting humans and a primary cause of death on a global scale. Chemotherapy continues to be one of the most essential cancer treatments, in addition to surgery and radiotherapy. Recently, the use of targeted anticancer medications as an approach for optimizing antitumor therapy has been advocated. One of the most wellestablished cancer targets is histone deacetylases (HDACs). HDAC inhibitors (HDACis) have evolved as one of the most effective anticancer medications due to their capacity to destroy cancer cells aggressively via alteration of the chromatin structure or inhibition of their activity. The discovery of selective HDACs has recently garnered considerable interest for their diverse biological activities and potential therapeutic agents with fewer adverse effects than approved pan inhibitors. This review provides an overview of isoform-and class-selective HDAC inhibitors, including the IC50 values and biological effects on various types of cancer.

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“…However, the therapeutic outcome from pan-HDACI SAHA is widely limited by its insufficient selectivity towards specific isoforms, resulting in many unwanted side effects, including dehydration, anorexia, thrombocytopenia, arrhythmia, and also poor pharmacokinetic (PK) profiles. Hence, intensive structural modifications have been carried out to procure more potent HDACIs with improved selectivity and less toxicity [12].…”

Section: Possible Biotargets and Related Lras 21 Histone Deacetylase ...mentioning

confidence: 99%

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

Wang

Wei

et al. 2022

Molecules

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The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called ‘shock-and-kill’ regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.

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Isoform-Selective Versus Nonselective Histone Deacetylase Inhibitors in HIV Latency Reversal

Cited by 7 publications

References 65 publications

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Recent review on selective histone deacetylase inhibitors in cancer therapy

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

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