A clue to unprecedented strategy to HIV eradication: “Lock-in and apoptosis”

Tateishi, Hiroshi; Monde, Kazuaki; Anraku, Kensaku; Koga, Ryoko; Hayashi, Yuya; Çiftçi, Halil; DeMi̇rci̇, Hasan; Higashi, Taishi; Motoyama, Keiichi; Arima, Hisatomi; Otsuka, Masami; Fujita, Mikako

doi:10.1038/s41598-017-09129-w

Cited by 50 publications

(52 citation statements)

References 28 publications

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“…The cells were analyzed by a fluorescence microscope Biorevo Fluorescence BZ‐9000 (Keyence). The number of apoptotic cells (Annexin V), late apoptotic or necrotic cells (Annexin V and Ethidium homodimer III), and necrotic cells (Ethidium homodimer III) were counted as previously described (Tateishi et al, ).…”

Section: Methodsmentioning

confidence: 99%

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

et al. 2020

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Herein, we report the synthesis and cytotoxic effects of novel chlorinated plastoquinone analogs (ABQ1–17) against different leukemic cells. Compounds ABQ3, ABQ11, and ABQ12 demonstrated a pronounced antiproliferative effect against chronic myelogenous leukemia (CML) K562 cell line with IC50 values of 0.82 ± 0.07, 0.28 ± 0.03, and 0.98 ± 0.22 μM, respectively. Among them, ABQ11 showed approximately three times higher selectivity than imatinib on CML. ABQ11‐treated CML cells induced significant apoptosis at low concentration. Inhibitory effect of ABQ11 against eight different tyrosine kinases, including ABL1, was investigated. ABQ11 inhibited ABL1 with IC50 value of 13.12 ± 1.71 μM, indicating that the moderate inhibition of ABL1 kinase is just an in‐part mechanism of its outstanding cellular activity. Molecular docking of ABQ11 into ABL1 kinase ATP‐binding pocket revealed the formation of some key interactions. Furthermore, DNA cleavage assay showed that ABQ11 strongly disintegrated DNA at 1 μM concentration in the presence of iron (II) complex system, assuming that the major mechanism for the anticancer effects of ABQ11 is DNA cleavage. In silico ADMET prediction revealed that ABQ11 is a drug‐like small molecule with a favorable safety profile. Taken together, ABQ11 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from imatinib.

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Section: Methodsmentioning

confidence: 99%

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

et al. 2020

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“…To this end, TLR agonists offer promise due to their ability to induce a broad anti-viral response, simultaneously activating virus production and priming immune clearance of HIV-1 infected cells (Borducchi et al, 2016;Tsai et al, 2017;Lim et al, 2018;Macedo et al, 2018). To circumvent the need for CTL mediated cell clearance altogether, an alternative approach is to block the release of virions and induce apoptosis of the infected cell (Tateishi et al, 2017). In this method, a novel compound is used to inhibit HIV-1 Pr55 Gag , blocking virus budding and leading to a build-up of viral products and subsequent apoptosis of the infected cell (Figure 1; Tateishi et al, 2017).…”

Section: Shock and Killmentioning

confidence: 99%

“…To circumvent the need for CTL mediated cell clearance altogether, an alternative approach is to block the release of virions and induce apoptosis of the infected cell (Tateishi et al, 2017). In this method, a novel compound is used to inhibit HIV-1 Pr55 Gag , blocking virus budding and leading to a build-up of viral products and subsequent apoptosis of the infected cell (Figure 1; Tateishi et al, 2017).…”

Section: Shock and Killmentioning

confidence: 99%

Measuring the Success of HIV-1 Cure Strategies

Thomas

Ruggiero

Paxton

et al. 2020

Front. Cell. Infect. Microbiol.

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HIV-1 eradication strategies aim to achieve viral remission in the absence of antiretroviral therapy (ART). The development of an HIV-1 cure remains challenging due to the latent reservoir (LR): long-lived CD4 T cells that harbor transcriptionally silent HIV-1 provirus. The LR is stable despite years of suppressive ART and is the source of rebound viremia following therapy interruption. Cure strategies such as "shock and kill" aim to eliminate or reduce the LR by reversing latency, exposing the infected cells to clearance via the immune response or the viral cytopathic effect. Alternative strategies include therapeutic vaccination, which aims to prime the immune response to facilitate control of the virus in the absence of ART. Despite promising advances, these strategies have been unable to significantly reduce the LR or increase the time to viral rebound but have provided invaluable insight in the field of HIV-1 eradication. The development and assessment of an HIV-1 cure requires robust assays that can measure the LR with sufficient sensitivity to detect changes that may occur following treatment. The viral outgrowth assay (VOA) is considered the gold standard method for LR quantification due to its ability to distinguish intact and defective provirus. However, the VOA is time consuming and resource intensive, therefore several alternative assays have been developed to bridge the gap between practicality and accuracy. Whilst a cure for HIV-1 infection remains elusive, recent advances in our understanding of the LR and methods for its eradication have offered renewed hope regarding achieving ART free viral remission.

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“…any of currently approved antiretroviral drugs [11][12][13]. Based on the structural information of the MA domain and PI(4,5)P2, we recently developed a non-natural derivative of PI(4,5)P2, named L-HIPPO, which binds to the MA domain in order to eradicate HIV [14,15]. Recent progress identifying cellular interactions of HIV-1 Gag has revealed that the MA domain of the Gag is capable of binding to inositol hexaphosphate (IP6) [14,16] ( Figure 2B & C).…”

Section: Introductionmentioning

confidence: 99%

Serial femtosecond X-ray diffraction of HIV-1 Gag MA-IP6 microcrystals at ambient temperature

Çiftçi

Sierra

Yoon

et al. 2019

Preprint

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The Human immunodeficiency virus-1 (HIV-1) matrix (MA) domain is involved in the highly regulated assembly process of the virus particles that occur at the host cell’s plasma membrane. High-resolution structures of the MA domain determined using cryo X- ray crystallography have provided initial insights into the possible steps in the viral assembly process. However, these structural studies have relied on large and frozen crystals in order to reduce radiation damage caused by the intense X-rays. Here, we report the first XFEL study of the HIV-1 MA domain’s interaction with inositol hexaphosphate (IP6), a phospholipid headgroup mimic. We also describe the purification, characterization and microcrystallization of two MA crystal forms obtained in the presence of IP6. In addition, we describe the capabilities of serial femtosecond X-ray crystallography (SFX) using X-ray free-electron laser (XFEL) to elucidate the diffraction data of MA-IP6 complex microcrystals in liquid suspension at ambient temperature. Two different microcrystal forms of MA-IP6 complex both diffracted to beyond 3.5 Å resolution, demonstrating the feasibility of using SFX to study the complexes of MA domain of HIV-1 Gag polyprotein with IP6 at near-physiological temperatures. Further optimization of the experimental and data analysis procedures will lead to better understanding of the MA domain of HIV-1 Gag and IP6 interaction at high resolution and provide basis for optimization of the lead compounds for efficient inhibition of the Gag protein recruitment to the plasma membrane prior to virion formation.

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A clue to unprecedented strategy to HIV eradication: “Lock-in and apoptosis”

Cited by 50 publications

References 28 publications

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

Measuring the Success of HIV-1 Cure Strategies

Serial femtosecond X-ray diffraction of HIV-1 Gag MA-IP6 microcrystals at ambient temperature

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