Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity

Trivedi, Jay; Parveen, Afsana; Rozy, Farhana; Mitra, Alapani; Bal, Chandralata; Mitra, Debashis; Sharon, Ashoke

doi:10.1016/j.ejmech.2019.111699

Cited by 15 publications

(5 citation statements)

References 51 publications

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“…With the use of latency–promoting agents (LPAs), the block–and–lock cure strategy strives to generate a cellular reservoir that is resistant to reactivation and unable to rebound after treatment interruption [ 222 , 223 , 224 ]. Several LPAs have been described, such as the Tat inhibitor didehydro–cortistatin A [ 225 , 226 ], curaxin CBL0100 [ 227 ], heat shock protein 90 (HSP90) inhibitors [ 228 ], Janus kinase signal transducer and activator of transcription (JAK–STAT) pathway inhibitors [ 229 ], mammalian target of rapamycin signaling inhibitors [ 230 ] and LEDGINs [ 22 , 23 , 77 ] (for a review, see [ 223 , 231 ]). In this review on retroviral integration, we will further discuss the block–and–lock functional cure with LEDGINs.…”

Section: Medical Applications Of Retroviral Integration Site Selectionmentioning

confidence: 99%

Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

Pellaers

Bhat

Christ

et al. 2022

Viruses

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To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection.

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Section: Medical Applications Of Retroviral Integration Site Selectionmentioning

confidence: 99%

Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

Pellaers

Bhat

Christ

et al. 2022

Viruses

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“…Another study has shown that the phenomenon of HSP90 co-localization with actively transcribing provirus is enhanced in hyperthermic conditions leading to increase in HIV-1 replication (Roesch et al 2012 ). Recently, we have reported that the LTR-driven gene expression is enhanced and suppressed by over-expression and silencing of HSP90 respectively in HEK293T cells and novel HSP90 inhibitors can suppress virus replication, indicating its possible use as a therapeutic target (Trivedi et al 2019 ). Like other elements of heat shock pathway namely heat shock factor-1 (HSF-1), HSP90 also governs HIV-1 reactivation from latent reservoirs present in resting host cells (Timmons et al 2020 ).…”

Section: Hspc Family (Hsp90)mentioning

confidence: 99%

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle

Iyer

Chand

Mitra

et al. 2021

Cell Stress and Chaperones

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Heat shock proteins (HSPs) are a group of cellular proteins that are induced during stress conditions such as heat stress, cold shock, UV irradiation and even pathogenic insult. They are classified into families based on molecular size like HSP27, 40, 70 and 90 etc, and many of them act as cellular chaperones that regulate protein folding and determine the fate of mis-folded or unfolded proteins. Studies have also shown multiple other functions of these proteins such as in cell signalling, transcription and immune response. Deregulation of these proteins leads to devastating consequences, such as cancer, Alzheimer’s disease and other life threatening diseases suggesting their potential importance in life processes. HSPs exist in multiple isoforms, and their biochemical and functional characterization still remains a subject of active investigation. In case of viral infections, several HSP isoforms have been documented to play important roles with few showing pro-viral activity whereas others seem to have an anti-viral role. Earlier studies have demonstrated that HSP40 plays a pro-viral role whereas HSP70 inhibits HIV-1 replication; however, clear isoform-specific functional roles remain to be established. A detailed functional characterization of all the HSP isoforms will uncover their role in cellular homeostasis and also may highlight some of them as potential targets for therapeutic strategies against various viral infections. In this review, we have tried to comprehend the details about cellular HSPs and their isoforms, their role in cellular physiology and their isoform-specific functions in case of virus infection with a specific focus on HIV-1 biology.

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“…Its impressive potency has led to its being valued in a phase II clinical trial 28,29 . Inspired by the therapeutic potential of isoxazole-based organic molecules [30][31][32][33] , and our previous successful experiences, 34,35 a new series of 3, 4-disubstituted isoxazole scaffolds were designed and synthesized through several steps. The efficacy of the synthesized molecules was evaluated by employing the MTT assay and Hsp90 molecular chaperone inhibition activity.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of new isoxazole derivatives as Hsp90 inhibitors

keshavarzipour,

Abbasi,

Khorsandi

et al. 2024

Preprint

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Heat shock protein 90 (Hsp90), a molecular chaperone, contributes to the preservation of folding, structure, stability, and function proteins. In this study, novel compounds comprising isoxazole structure were designed, synthesized and their potential ability as Hsp90 inhibitors was validated through docking studies. The active site-based compounds were prepared through a multi-step synthesis process and their chemical structures were characterized employing FT-IR, NMR, and mass spectrometry analysis. Cytotoxic and Hsp90 inhibition activities of synthesized compounds were assessed by MTT assay and ELISA kit, respectively. Based on the obtained results, compound 5 was the most cytotoxic derivative (IC50; 14 µM) against cancer cells and reduced Hsp90 expression from 5.54 ng/ml in untreated (normal cells) to 1.56 ng/ml in cancer cells. Moreover, molecular dynamics (MD) simulation results indicated its high affinity to target protein and approved its excellent stability which is essential for exerting an inhibitory effect on cancer cell proliferation.

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Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity

Cited by 15 publications

References 51 publications

Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle

Design, synthesis and biological evaluation of new isoxazole derivatives as Hsp90 inhibitors

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