Synthetic Caged DAG‐lactones for Photochemically Controlled Activation of Protein Kinase C

Nomura, Wataru; Narumi, Tetsuo; Ohashi, Nobukimi; Serizawa, Yuki; Lewin, Nancy E.; Blumberg, Peter M.; Furuta, Toshiaki; Tamamura, Hirokazu

doi:10.1002/cbic.201000670

Cited by 20 publications

(31 citation statements)

References 46 publications

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“…Additionally, reversibly controlled protein kinase C (PKC) localization and activation at the membrane was demonstrated. Previously, PKC and C1 domains have been controlled through the introduction of nitrobenzyl and coumarin caging groups on dioctanoyl glycerol or through bromohydroxycoumarin‐caged DAG lactones; however these methods only allow off‐to‐on activation. The azobenzene‐based system described above provides multiple cycles of recruitment/activation and dissociation/inactivation in an innovative approach (see Section 3.3 for a further discussion of the advantages of reversible photoswitching of cellular processes).…”

Section: Optical Control Of Small Moleculesmentioning

confidence: 99%

Optochemical Control of Biological Processes in Cells and Animals

et al. 2018

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Biological processes are naturally regulated with high spatial and temporal control, as is perhaps most evident in metazoan embryogenesis. Chemical tools have been extensively utilized in cell and developmental biology to investigate cellular processes, and conditional control methods have expanded applications of these technologies toward resolving complex biological questions. Light represents an excellent external trigger since it can be controlled with very high spatial and temporal precision. To this end, several optically regulated tools have been developed and applied to living systems. In this review we discuss recent developments of optochemical tools, including small molecules, peptides, proteins, and nucleic acids that can be irreversibly or reversibly controlled through light irradiation, with a focus on applications in cells and animals.

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Section: Optical Control Of Small Moleculesmentioning

confidence: 99%

Optochemical Control of Biological Processes in Cells and Animals

et al. 2018

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“…A panel of DAG-lactone derivatives, including YSE028, was synthesized as described previously Tamamura et al, 2000;Nomura et al, 2011;Figure 1A). Prostratin (PKC activator), PEP005 (PKC activator), and JQ-1 (BET inhibitor) were purchased from Sigma-Aldrich (St. Louis, MO, United States), Cyman Chemical (Ann Arbor, MI, United States), and BioVision (Milpitas, CA, United States), respectively.…”

Section: Drugs and Reagentsmentioning

confidence: 99%

“…In this study, we focused on the HIV-1 latency-reversing activity and safety of DAG-lactone derivatives, including YSE028 (Nomura et al, 2011), which exhibited a potent ability to activate latent HIV-1 infected cells without any toxicity in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators

et al. 2021

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Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent in vitro and in vivo studies have raised serious concerns regarding the efficacy and safety of the “shock and kill” strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency in vitro when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity in vitro and in vivo. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.

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“…Additionally, reversibly controlled protein kinase C (PKC) localization and activation at the membrane was demonstrated. Previously, PKC and C1 domains have been controlled through introduction of nitrobenzyl and coumarin caging groups on dioctanoyl glycerol [35] or through bromohydroxycoumarin caged DAG-lactones; [36] however, these methods only allowed for off-to-on activation. The azobenzene-based system established here provides multiple cycles of recruitment/activation and dissociation/inactivation in an innovative approach (see Section 3.3 for a further discussion of the advantages of reversible photoswitching of cellular processes).…”

Section: Engineering Pharmacophores For Reversible Photoswitching Of mentioning

confidence: 99%

Optochemische Steuerung biologischer Vorgänge in Zellen und Tieren

et al. 2018

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This article is protected by copyright. All rights reserved optochemical control of biology. In contrast to excellent previous reviews that focus on the chemistry of controlling biological function with light, [1] this review focuses on manipulation of cell and animal biology using photochemical approaches. Purely optogenetic approaches, not utilizing chemical operations, have been reviewed elsewhere. [2] 2. Optical control of small molecules Small molecule probes have been essential tools to perturb and control cellular processes, thereby providing an understanding of detailed biological function. Optical control of small molecule function provides an extra layer of precision to the molecular toolbox by enabling temporal and spatial control with high resolution, as discussed in the examples below. Small molecule protein dimerizers, inhibitors, metabolites, and metal ions have all been rendered lightresponsive through the chemical installation of caging groups and have been applied to the investigation of living systems. In contrast to photocaged nucleic acids, peptides, and proteins, small molecules have the added benefits of being synthetically more accessible and capable of being readily delivered into cells and animals. 2.1. Optical activation of rapamycin induced dimerization Chemical inducers of dimerization (CIDs) are prominent tools for chemical biologists to place biological processes under conditional control. [3] The most commonly utilized CID is rapamycin, which binds to FK506 binding protein (FKBP) and the FKBP-rapamycin binding domain of mTOR (FRB), forming a ternary complex. Due to the small size of FKBP and FRB, these domains have been fused to numerous proteins and subsequent heterodimerization was induced by rapamycin. Processes that have been placed under rapamycin control include Golgi/endoplasmic reticulum association to study mitosis, [4] phosphoinositide control of endocytic trafficking, [5] and inactivation of proteins by rerouting them to the mitochondria. [6] Caged rapamycin analogs allow for placement of these processes under optical control in order to enhance temporal and spatial resolution. The photocaged rapamycin analog 1 was generated through installation of a nitrobenzyl caging group at the C-40 position (Figure 1a). [7] When applied to cells, 1 still induced FKBP-FRB dimerization, indicating that the caging group alone wasn't sufficient to abrogate protein-small molecule interaction, which is consistent with previous modifications at C-40. [8] However, work by the Hahn lab had shown that a truncated FKBP, termed iFKBP, [9] exhibited increased flexibility in the loop that interacts with the C-40 position of rapamycin. This flexibility increased contacts for interaction with 1 and resulted in a distorted binding conformation that prevented formation of the ternary complex consisting of iFKBP, FRB, and 1. This system was then applied to the optical activation of FAK (focal adhesion kinase), using an engineered iFKBP-FAK fusion which rendered the kinase inactive until UV irradiation...

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Synthetic Caged DAG‐lactones for Photochemically Controlled Activation of Protein Kinase C

Cited by 20 publications

References 46 publications

Optochemical Control of Biological Processes in Cells and Animals

Optochemical Control of Biological Processes in Cells and Animals

A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators

Optochemische Steuerung biologischer Vorgänge in Zellen und Tieren

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