The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Motomasa Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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short step synthesis and structure activity relationship of Cortistatin a analogs
Tetrahedron, 2017Co-Authors: Naoyuki Kotoku, Aoi Ito, Shunichi Shibuya, Kanako Mizuno, Aki Takeshima, Masaki Nogata, Motomasa KobayashiAbstract:Abstract An improved method for synthesizing structurally simplified analogs of Cortistatin A (1), a novel anti-angiogenic steroidal alkaloid from a marine sponge, was developed. In contrast to previous methods, step- and redox-economical synthesis was achieved using a known α-bromoketone as the starting material. The structure-activity relationship study revealed that the isoquinoline portion was strictly recognized by the target molecule. Surprisingly, the introduction of the acetamide moiety on the A-ring structure dramatically enhanced the selective antiproliferative activity against endothelial cells. This new method can be easily applied to gram-scale synthesis and enabled us to prepare various analogs, which were focused on the participation of the side chain and A-ring structure.
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synthetic studies of Cortistatin a analogue from the cd ring fragment of vitamin d2
Chemical & Pharmaceutical Bulletin, 2013Co-Authors: Naoyuki Kotoku, Kohei Mizushima, Satoru Tamura, Motomasa KobayashiAbstract:Syntheses of analogue compounds of Cortistatin A (1), an anti-angiogenic steroidal alkaloid from Indonesian marine sponge, were investigated by utilizing the CD-ring fragment of vitamin D₂. The incidental preparation of a new analogue having CD-cis-fused skeleton and its biological evaluation revealed the importance of the CD-trans-fused structure for the potent and selective antiproliferative activity of 1 against human umbilical vein endothelial cells (HUVECs).
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creation of readily accessible and orally active analogue of Cortistatin a
ACS Medicinal Chemistry Letters, 2012Co-Authors: Naoyuki Kotoku, Yuji Sumii, Masayoshi Arai, Takeshi Hayashi, Satoru Tamura, Takashi Kawachi, Sho Shiomura, Motomasa KobayashiAbstract:Syntheses of structurally simplified analogues of Cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of 1. Compound 30, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed in vivo antiangiogenic activity and significant antitumor effect by oral administration.
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Stereoselective synthesis of core structure of Cortistatin A.
Organic Letters, 2011Co-Authors: Naoyuki Kotoku, Yuji Sumii, Motomasa KobayashiAbstract:A stereoselective synthesis of the core structure of Cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck cyclization and a subsequent acid-mediated oxy-Michael reaction.
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synthesis of cd ring structure of Cortistatin a an anti angiogenic steroidal alkaloid from marine sponge
Tetrahedron Letters, 2008Co-Authors: Naoyuki Kotoku, Yuji Sumii, Takeshi Hayashi, Motomasa KobayashiAbstract:Abstract Stereoselective synthesis of the CD-ring structure of Cortistatin A (1), a novel anti-angiogenic steroidal alkaloid from Indonesian marine sponge, was achieved. The stereogenic tertiary carbon center bearing the isoquinoline moiety was constructed by 1,3-chiral transfer method using Johnson–Claisen rearrangement of the chiral allylic alcohol 5. Subsequent intramolecular Michael-aldol reaction afforded the targeted trans-hydrindane skeleton with moderate stereoselectivity.
Luis De Lecea - One of the best experts on this subject based on the ideXlab platform.
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fasting modulates gh igf i axis and its regulatory systems in the mammary gland of female mice influence of endogenous Cortistatin
Molecular and Cellular Endocrinology, 2016Co-Authors: Alicia Villaosaba, Luis De Lecea, Justo P Castano, Manuel D Gahete, Jose Cordobachacon, Raul M LuqueAbstract:Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/Cortistatin and ghrelin) in MG during fasting. Therefore, this study was aimed at characterizing the regulation of GH/IGF-I/somatostatin/Cortistatin/ghrelin-systems expression in MG of fasted female-mice (compared to fed-controls) and the influence of endogenous-Cortistatin (using Cortistatin-knockouts). Fasting decreased IGF-I while increased IGF-I/Insulin-receptors expression in MGs. Fasting provoked an increase in GH expression that might be associated to enhanced ghrelin-variants/ghrelin-O-acyl-transferase enzyme expression, while an upregulation of somatostatin-receptors was observed. However, Cortistatin-knockouts mice showed a decrease in GH and somatostatin receptor-subtypes expression. Altogether, we demonstrate that GH/IGF-I, somatostatin/Cortistatin and ghrelin systems expression is altered in MG during fasting, suggesting a relevant role in coordinating its response to metabolic stress, wherein endogenous Cortistatin might be essential for an appropriate response.
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Cortistatin is a key factor regulating the sex dependent response of the gh and stress axes to fasting in mice
Endocrinology, 2016Co-Authors: Jose Cordobachacon, Luis De Lecea, Justo P Castano, Manuel D Gahete, Ana I Pozosalas, Raul M LuqueAbstract:Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST) but displays unique sex-dependent pituitary actions. Indeed, although female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, Proopiomelanocortin expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plasma GH/corticosterone levels. Changes in peripheral ghrelin and SST (rather than hypothalamic levels) seem to regulate GH/ACTH axes in CORT-KOs under fed conditions. Because changes in GH/ACTH axes during fasting provide important adaptive mechanisms, we sought to determine whether CORT absence influences GH/ACTH axes during fasting. Accordingly, fed and fasted male/female CORT-KO were compared with littermate controls. Fasting increased circulating GH levels in male/female controls but not in CORT-KO, suggesting that CORT can be a relevant regulator of GH secretion during fasting. However, GH levels were already higher in CORT-KO than in con...
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Cortistatin attenuates inflammatory pain via spinal and peripheral actions
Neurobiology of Disease, 2014Co-Authors: Maria Morell, Luis De Lecea, Michael D Culler, Maria Camprubirobles, Mario DelgadoAbstract:Clinical pain, as a consequence of inflammation or injury of peripheral organs (inflammatory pain) or nerve injury (neuropathic pain), represents a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. To limit duration and intensity of pain, inhibitory signals participate in pain perception. Cortistatin is a cyclic-neuropeptide that exerts potent inhibitory actions on cortical neurons and immune cells. Here, we found that Cortistatin is a natural analgesic component of the peripheral nociceptive system produced by peptidergic nociceptive neurons of the dorsal root ganglia in response to inflammatory and noxious stimuli. Moreover, Cortistatin is produced by GABAergic interneurons of deep layers of dorsal horn of spinal cord. By using Cortistatin-deficient mice, we demonstrated that endogenous Cortistatin critically tunes pain perception in physiological and pathological states. Furthermore, peripheral and spinal injection of Cortistatin potently reduced nocifensive behavior, heat hyperalgesia and tactile allodynia in experimental models of clinical pain evoked by chronic inflammation, surgery and arthritis. The analgesic effects of Cortistatin were independent of its anti-inflammatory activity and directly exerted on peripheral and central nociceptive terminals via Gαi-coupled somatostatin-receptors (mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including protein kinase A-, calcium- and Akt/ERK-mediated release of nociceptive peptides. Moreover, Cortistatin could modulate, through its binding to ghrelin-receptor (GHSR1), pain-induced sensitization of secondary neurons in spinal cord. Therefore, Cortistatin emerges as an anti-inflammatory factor with potent analgesic effects that offers a new approach to clinical pain therapy, especially in inflammatory states.
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paradoxical effect of Cortistatin treatment and its deficiency on experimental autoimmune encephalomyelitis
Journal of Immunology, 2013Co-Authors: Luciana Souzamoreira, Raul M Luque, Maria Morell, Virginia Delgadomaroto, Marta Pedreno, Laura Martinezescudero, Marta Caro, Francisco Ovalle, Milagros Gallo, Luis De LeceaAbstract:Cortistatin is a cyclic-neuropeptide produced by brain cortex and immune cells that shows potent anti-inflammatory activity. In this article, we investigated the effect of Cortistatin in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short-term systemic treatment with Cortistatin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord, and the subsequent demyelination and axonal damage. This effect was associated with a reduction of the two deleterious components of the disease, namely, the autoimmune and inflammatory response. Cortistatin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, and downregulated various inflammatory mediators, whereas it increased the number of regulatory T cells with suppressive effects on the encephalitogenic response. Moreover, Cortistatin regulated glial activity and favored an active program of neuroprotection/regeneration. We further used Cortistatin-deficient mice to investigate the role of endogenous Cortistatin in the control of immune responses. Surprisingly, Cortistatin-deficient mice were partially resistant to EAE and other inflammatory disorders, despite showing competent inflammatory/autoreactive responses. This unexpected phenotype was associated with elevated circulating glucocorticoids and an anxiety-like behavior. Our findings provide a powerful rationale for the assessment of the efficacy of Cortistatin as a novel multimodal therapeutic approach to treat multiple sclerosis and identify Cortistatin as a key endogenous component of neuroimmune system.
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analgesic effect of the neuropeptide Cortistatin in murine models of arthritic inflammatory pain
Arthritis & Rheumatism, 2013Co-Authors: Maria Morell, Luis De Lecea, Luciana Souzamoreira, Marta Caro, Francisco Ovalle, Irene Fortelago, Elena Gonzalezrey, Mario DelgadoAbstract:Objective To investigate the role of the antiinflammatory neuropeptide Cortistatin in chronic pain evoked by joint inflammation. Methods Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of Cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of Cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous Cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in Cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of Cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Results Expression of Cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous Cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that Cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of Cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi, impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. Conclusion These findings indicate that Cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory states, including osteoarthritis and rheumatoid arthritis.
Mario Delgado - One of the best experts on this subject based on the ideXlab platform.
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protective role of Cortistatin in pulmonary inflammation and fibrosis
British Journal of Pharmacology, 2021Co-Authors: Margarita Barriga, Marta Caro, Raquel Benitez, V Ferrazdepaula, Marina Garciafrutos, Gema Robledo, Francisco O Valle, Jenny Campossalinas, Mario DelgadoAbstract:BACKGROUND AND PURPOSE: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and healthcare burden in the critically ill patient. There is an urgent medical need for identifying factors of susceptibility and prognosis and for designing new therapeutic tools for treating these disorders. Here, we evaluate the capacity of the immunomodulatory neuropeptide Cortistatin to regulate pulmonary inflammation and fibrosis in vivo. EXPERIMENTAL APPROACH: ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and Cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines and fibrotic markers were evaluated. KEY RESULTS: Partially-deficient mice in Cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with Cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis after high-exposition to both injury agents. Moreover, Cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with Cortistatin impaired their activation. Finally, the protective effects of Cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin- and ghrelin-receptors. CONCLUSION AND IMPLICATIONS: We identify to Cortistatin as an endogenous break of pulmonary inflammation and fibrosis. Deficiency in Cortistatin could be a marker of poor-prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies emerge as attractive candidates to treat severe ALI/ARDS, including SARS-Cov-2-associated ARDS.
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the neuropeptide Cortistatin alleviates neuropathic pain in experimental models of peripheral nerve injury
Pharmaceutics, 2021Co-Authors: C P Falo, Maria Morell, Marta Caro, Francisco Ovalle, Irene Fortelago, Mario Delgado, Pedro Hernandezcortes, Raquel Benitez, Clara Sanchezgonzalez, Elena GonzalezreyAbstract:Neuropathic pain is one of the most severe forms of chronic pain caused by the direct injury of the somatosensory system. The current drugs for treating neuropathies have limited efficacies or show important side effects, and the development of analgesics with novel modes of action is critical. The identification of endogenous anti-nociceptive factors has emerged as an attractive strategy for designing new pharmacological approaches to treat neuropathic pain. Cortistatin is a neuropeptide with potent anti-inflammatory activity, recently identified as a natural analgesic peptide in several models of pain evoked by inflammatory conditions. Here, we investigated the potential analgesic effect of Cortistatin in neuropathic pain using a variety of experimental models of peripheral nerve injury caused by chronic constriction or partial transection of the sciatic nerve or by diabetic neuropathy. We found that the peripheral and central injection of Cortistatin ameliorated hyperalgesia and allodynia, two of the dominant clinical manifestations of chronic neuropathic pain. Cortistatin-induced analgesia was multitargeted, as it regulated the nerve damage-induced hypersensitization of primary nociceptors, inhibited neuroinflammatory responses, and enhanced the production of neurotrophic factors both at the peripheral and central levels. We also demonstrated the neuroregenerative/protective capacity of Cortistatin in a model of severe peripheral nerve transection. Interestingly, the nociceptive system responded to nerve injury by secreting Cortistatin, and a deficiency in Cortistatin exacerbated the neuropathic pain responses and peripheral nerve dysfunction. Therefore, Cortistatin-based therapies emerge as attractive alternatives for treating chronic neuropathic pain of different etiologies.
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lulling immunity pain and stress to sleep with Cortistatin
Annals of the New York Academy of Sciences, 2015Co-Authors: Elena Gonzalezrey, Luciana Souzamoreira, Virginia Delgadomaroto, Marta Pedreno, Mario DelgadoAbstract:Cortistatin is a neuropeptide isolated from cortical brain regions, showing high structural homology and sharing many functions with somatostatin. However, Cortistatin exerts unique functions in the central nervous and immune systems, including decreasing locomotor activity, inducing sleep-promoting effects, and deactivating inflammatory and T helper (TH)1/TH17–driven responses in preclinical models of sepsis, arthritis, multiple sclerosis, and colitis. Besides its release by cortical and hippocampal interneurons, Cortistatin is produced by macrophages, lymphocytes, and peripheral nociceptive neurons in response to inflammatory stimuli, supporting a physiological role of Cortistatin in the immune and nociceptive systems. Cortistatin-deficient mice have been shown to have exacerbated nociceptive responses to neuropathic and inflammatory pain sensitization. However, a paradoxical effect has been observed in studies of immune disorders, in which, despite showing competent inflammatory/autoreactive responses, Cortistatindeficient mice were partially resistant to systemic autoimmunity and inflammation. This unexpected phenotype was associated with elevated circulating glucocorticoids and anxiety-like behavior. These findings support Cortistatin as a novel multimodal therapeutic approach to treat autoimmunity and clinical pain and identify it as a key endogenous component of the neuroimmune system related to stress responses.
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Cortistatin attenuates inflammatory pain via spinal and peripheral actions
Neurobiology of Disease, 2014Co-Authors: Maria Morell, Luis De Lecea, Michael D Culler, Maria Camprubirobles, Mario DelgadoAbstract:Clinical pain, as a consequence of inflammation or injury of peripheral organs (inflammatory pain) or nerve injury (neuropathic pain), represents a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. To limit duration and intensity of pain, inhibitory signals participate in pain perception. Cortistatin is a cyclic-neuropeptide that exerts potent inhibitory actions on cortical neurons and immune cells. Here, we found that Cortistatin is a natural analgesic component of the peripheral nociceptive system produced by peptidergic nociceptive neurons of the dorsal root ganglia in response to inflammatory and noxious stimuli. Moreover, Cortistatin is produced by GABAergic interneurons of deep layers of dorsal horn of spinal cord. By using Cortistatin-deficient mice, we demonstrated that endogenous Cortistatin critically tunes pain perception in physiological and pathological states. Furthermore, peripheral and spinal injection of Cortistatin potently reduced nocifensive behavior, heat hyperalgesia and tactile allodynia in experimental models of clinical pain evoked by chronic inflammation, surgery and arthritis. The analgesic effects of Cortistatin were independent of its anti-inflammatory activity and directly exerted on peripheral and central nociceptive terminals via Gαi-coupled somatostatin-receptors (mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including protein kinase A-, calcium- and Akt/ERK-mediated release of nociceptive peptides. Moreover, Cortistatin could modulate, through its binding to ghrelin-receptor (GHSR1), pain-induced sensitization of secondary neurons in spinal cord. Therefore, Cortistatin emerges as an anti-inflammatory factor with potent analgesic effects that offers a new approach to clinical pain therapy, especially in inflammatory states.
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analgesic effect of the neuropeptide Cortistatin in murine models of arthritic inflammatory pain
Arthritis & Rheumatism, 2013Co-Authors: Maria Morell, Luis De Lecea, Luciana Souzamoreira, Marta Caro, Francisco Ovalle, Irene Fortelago, Elena Gonzalezrey, Mario DelgadoAbstract:Objective To investigate the role of the antiinflammatory neuropeptide Cortistatin in chronic pain evoked by joint inflammation. Methods Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of Cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of Cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous Cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in Cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of Cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Results Expression of Cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous Cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that Cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of Cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi, impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. Conclusion These findings indicate that Cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory states, including osteoarthritis and rheumatoid arthritis.
Guillaume Mousseau - One of the best experts on this subject based on the ideXlab platform.
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resistance to the tat inhibitor didehydro Cortistatin a is mediated by heightened basal hiv 1 transcription
Mbio, 2019Co-Authors: Guillaume Mousseau, Sonia Mediouni, Cari F Kessing, Mark A Clementz, Rachna Aneja, Noemia S Lima, Alexander Haregot, Joseph A JablonskiAbstract:Human immunodeficiency virus type 1 (HIV-1) Tat binds the viral RNA structure transactivation-responsive element (TAR) and recruits transcriptional cofactors, amplifying viral mRNA expression. The Tat inhibitor didehydro-Cortistatin A (dCA) promotes a state of persistent latency, refractory to viral reactivation. Here we investigated mechanisms of HIV-1 resistance to dCA in vitro Mutations in Tat and TAR were not identified, consistent with the high level of conservation of these elements. Instead, viruses resistant to dCA developed higher Tat-independent basal transcription. We identified a combination of mutations in the HIV-1 promoter that increased basal transcriptional activity and modifications in viral Nef and Vpr proteins that increased NF-κB activity. Importantly, these variants are unlikely to enter latency due to accrued transcriptional fitness and loss of sensitivity to Tat feedback loop regulation. Furthermore, cells infected with these variants become more susceptible to cytopathic effects and immune-mediated clearance. This is the first report of viral escape to a Tat inhibitor resulting in heightened Tat-independent activity, all while maintaining wild-type Tat and TAR.IMPORTANCE HIV-1 Tat enhances viral RNA transcription by binding to TAR and recruiting activating factors. Tat enhances its own transcription via a positive-feedback loop. Didehydro-Cortistatin A (dCA) is a potent Tat inhibitor, reducing HIV-1 transcription and preventing viral rebound. dCA activity demonstrates the potential of the "block-and-lock" functional cure approaches. We investigated the viral genetic barrier to dCA resistance in vitro While mutations in Tat and TAR were not identified, mutations in the promoter and in the Nef and Vpr proteins promoted high Tat-independent activity. Promoter mutations increased the basal transcription, while Nef and Vpr mutations increased NF-κB nuclear translocation. This heightened transcriptional activity renders CD4+ T cells infected with these viruses more susceptible to cytotoxic T cell-mediated killing and to cell death by cytopathic effects. Results provide insights on drug resistance to a novel class of antiretrovirals and reveal novel aspects of viral transcriptional regulation.
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the tat inhibitor didehydro Cortistatin a suppresses siv replication and reactivation
The FASEB Journal, 2019Co-Authors: Sonia Mediouni, Cari F Kessing, Joseph A Jablonski, Suzie Theninhoussier, Mark A Clementz, Melia D Kovach, Guillaume Mousseau, Ian Mitchelle S De Vera, Douglas J Kojetin, David T EvansAbstract:The HIV-1 transactivation protein (Tat) binds the HIV mRNA transactivation responsive element (TAR), regulating transcription and reactivation from latency. Drugs against Tat are unfortunately not clinically available. We reported that didehydro-Cortistatin A (dCA) inhibits HIV-1 Tat activity. In human CD4+ T cells isolated from aviremic individuals and in the humanized mouse model of latency, combining dCA with antiretroviral therapy accelerates HIV-1 suppression and delays viral rebound upon treatment interruption. This drug class is amenable to block-and-lock functional cure approaches, aimed at a durable state of latency. Simian immunodeficiency virus (SIV) infection of rhesus macaques (RhMs) is the best-characterized model for AIDS research. Here, we demonstrate, using in vitro and cell-based assays, that dCA directly binds to SIV Tat's basic domain. dCA specifically inhibits SIV Tat binding to TAR, but not a Tat-Rev fusion protein, which activates transcription when Rev binds to its cognate RNA binding site replacing the apical region of TAR. Tat-TAR inhibition results in loss of RNA polymerase II recruitment to the SIV promoter. Importantly, dCA potently inhibits SIV reactivation from latently infected Hut78 cells and from primary CD4+ T cells explanted from SIVmac239-infected RhMs. In sum, dCA's remarkable breadth of activity encourages SIV-infected RhM use for dCA preclinical evaluation.-Mediouni, S., Kessing, C. F., Jablonski, J. A., Thenin-Houssier, S., Clementz, M., Kovach, M. D., Mousseau, G., de Vera, I.M.S., Li, C., Kojetin, D. J., Evans, D. T., Valente, S. T. The Tat inhibitor didehydro-Cortistatin A suppresses SIV replication and reactivation.
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in vivo suppression of hiv rebound by didehydro Cortistatin a a block and lock strategy for hiv 1 treatment
Cell Reports, 2017Co-Authors: Cari F Kessing, Guillaume Mousseau, Lydie Trautmann, Christopher C Nixon, Perry Tsai, Hiroshi Takata, Jenna B Honeycutt, Mohammad FallahiAbstract:HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4+ T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation. We show that dCA mediates epigenetic silencing by increasing nucleosomal occupancy at Nucleosome-1, restricting RNAPII recruitment to the HIV-1 promoter. The efficacy of dCA was studied in the bone marrow-liver-thymus (BLT) mouse model of HIV latency and persistence. Adding dCA to ART-suppressed mice systemically reduces viral mRNA in tissues. Moreover, dCA significantly delays and reduces viral rebound levels upon treatment interruption. Altogether, this work demonstrates the potential of block-and-lock cure strategies.
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didehydro Cortistatin a a new player in hiv therapy
Expert Review of Anti-infective Therapy, 2016Co-Authors: Guillaume Mousseau, Susana T ValenteAbstract:Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected CD4(+)T cells persists under suppressive therapy, and infected individuals must remain indefinitely on antiretroviral therapy to prevent viral reactivation and propagation. Despite therapy, some degree of low-level ongoing replication is detected and transient viral reactivation may replenish the latent reservoir. An analog of the natural compound, Cortistatin A, blocks HIV-1 transcription by specifically targeting the viral transactivator, Tat. Treatment of latently infected cells with this Tat inhibitor promotes a state of deep-latency from which HIV reactivation capacity is greatly diminished. Here we discuss the use of Tat inhibitors to limit the latent reservoir to achieve a functional cure.
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the tat inhibitor didehydro Cortistatin a prevents hiv 1 reactivation from latency
Mbio, 2015Co-Authors: Guillaume Mousseau, Cari F Kessing, Remi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T ValenteAbstract:Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4(+) T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-Cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4(+) T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. Importance Antiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4(+) T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-Cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.
Susana T Valente - One of the best experts on this subject based on the ideXlab platform.
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the block and lock strategy for human immunodeficiency virus cure lessons learned from didehydro Cortistatin a
The Journal of Infectious Diseases, 2021Co-Authors: Luisa Mori, Susana T ValenteAbstract:Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) infection. However, a reservoir of latently infected cells persists under suppressive therapy, constituting a major barrier to an HIV cure. The block-and-lock approach to a functional cure aims at the transcriptional and epigenetic silencing of proviruses, blocking viral reactivation in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. This approach has been put forward for exploration based on the activity of didehydro-Cortistatin A, an inhibitor of the HIV transcriptional activator Tat. Here we review the mechanisms by which didehydro-Cortistatin A inhibition of Tat's feedback loop transcriptional amplification results in epigenetic silencing of the HIV promoter, and we discuss the benefits and limitations of the block-and-lock approach for an HIV cure.
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didehydro Cortistatin a a new player in hiv therapy
Expert Review of Anti-infective Therapy, 2016Co-Authors: Guillaume Mousseau, Susana T ValenteAbstract:Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected CD4(+)T cells persists under suppressive therapy, and infected individuals must remain indefinitely on antiretroviral therapy to prevent viral reactivation and propagation. Despite therapy, some degree of low-level ongoing replication is detected and transient viral reactivation may replenish the latent reservoir. An analog of the natural compound, Cortistatin A, blocks HIV-1 transcription by specifically targeting the viral transactivator, Tat. Treatment of latently infected cells with this Tat inhibitor promotes a state of deep-latency from which HIV reactivation capacity is greatly diminished. Here we discuss the use of Tat inhibitors to limit the latent reservoir to achieve a functional cure.
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the tat inhibitor didehydro Cortistatin a prevents hiv 1 reactivation from latency
Mbio, 2015Co-Authors: Guillaume Mousseau, Cari F Kessing, Remi Fromentin, Lydie Trautmann, Nicolas Chomont, Susana T ValenteAbstract:Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4(+) T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-Cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4(+) T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. Importance Antiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4(+) T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-Cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.
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didehydro Cortistatin a inhibits hiv 1 tat mediated neuroinflammation and prevents potentiation of cocaine reward in tat transgenic mice
Current HIV Research, 2015Co-Authors: Sonia Mediouni, Joseph A Jablonski, Suzie Theninhoussier, Mark A Clementz, Jason J Paris, Jay P Mclaughlin, Susana T ValenteAbstract:HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.
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an analog of the natural steroidal alkaloid Cortistatin a potently suppresses tat dependent hiv transcription
Cell Host & Microbe, 2012Co-Authors: Guillaume Mousseau, Phil S Baran, Mark A Clementz, Remi Fromentin, Nicolas Chomont, Wendy Bakeman, Nisha Nagarsheth, Michael D Cameron, Susana T ValenteAbstract:Summary The human immunodeficiency virus type 1 (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5′-terminal region of HIV mRNA's stem-bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription. We find that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid from a marine sponge, inhibits Tat-mediated transactivation of the integrated provirus by binding specifically to the TAR-binding domain of Tat. Working at subnanomolar concentrations, dCA reduces Tat-mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, dCA abrogates spontaneous viral particle release from CD4 + T cells from virally suppressed subjects on highly active antiretroviral therapy (HAART). Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART.
