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https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#1
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28610952/structural-diversity-of-marine-cyclic-peptides-and-their-molecular-mechanisms-for-anticancer-antibacterial-antifungal-and-other-clinical-applications
#2
REVIEW
Yeji Lee, Chanvorleak Phat, Soon-Cheol Hong
Many cyclic peptides and analogues derived from marine sources are known to possess biological properties, including anticancer, antitumor, antibacterial, antifungal, antiparasitic, anti-inflammation, anti-proliferative, anti-hypertensive, cytotoxic, and antibiotic properties. These compounds demonstrate different activities and modes of action according to their structure such as cyclic oligopeptide, cyclic lipopeptide, cyclic glycopeptide and cyclic depsipeptide. The recent advances in application of the above-mentioned cyclic peptides were reported in dolastatins, soblidotin, didemnin B, aplidine, salinosporamide A, kahalalide F and bryostatin 1 and they are currently in clinical trials...
June 10, 2017: Peptides
https://www.readbyqxmd.com/read/28590053/bryostatin-and-its-synthetic-analog-picolog-rescue-dermal-fibroblasts-from-prolonged-stress-and-contribute-to-survival-and-rejuvenation-of-human-skin-equivalents
#3
Tapan K Khan, Paul A Wender, Daniel L Alkon
Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation...
June 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28539614/the-ccr5-antagonist-maraviroc-reverses-hiv-1-latency-in-vitro-alone-or-in-combination-with-the-pkc-agonist-bryostatin-1
#4
María Rosa López-Huertas, Laura Jiménez-Tormo, Nadia Madrid-Elena, Carolina Gutiérrez, Sara Rodríguez-Mora, Mayte Coiras, José Alcamí, Santiago Moreno
A potential strategy to cure HIV-1 infection is to use latency reversing agents (LRAs) to eliminate latent reservoirs established in resting CD4+ T (rCD4+) cells. As no drug has been shown to be completely effective, finding new drugs and combinations are of increasing importance. We studied the effect of Maraviroc (MVC), a CCR5 antagonist that activates NF-κB, on HIV-1 replication from latency. HIV-1-latency models based on CCL19 or IL7 treatment, before HIV-1 infection were used. Latently infected primary rCD4+ or central memory T cells were stimulated with MVC alone or in combination with Bryostatin-1, a PKC agonist known to reverse HIV-1 latency...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28482641/bryostatin-effects-on-cognitive-function-and-pkc%C3%A9-in-alzheimer-s-disease-phase-iia-and-expanded-access-trials
#5
Thomas J Nelson, Miao-Kun Sun, Chol Lim, Abhik Sen, Tapan Khan, Florin V Chirila, Daniel L Alkon
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28472666/effects-of-chronic-bryostatin-1-on-treatment-resistant-depression-in-rats
#6
Daniel L Alkon, Jarin Hongpaisan, Miao-Kun Sun
Despite over a half-century's intensive research worldwide, the currently available antidepressants remain sub-optimal. Therapeutic options for treatment-resistant depression, for instance, are rather limited. Here, we found that rats exhibited a lasting treatment-resistant depressive immobility in response to open space swim test at a high intensity of induction. The induced depressive behavior is associated with a dramatic impairment in spatial learning and memory. Both the depressive immobility and impairment in spatial learning and memory are sensitive to a period of chronic treatment with bryopstatin-1, a relatively selective activator of protein kinase Cε...
July 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28467486/the-effect-of-ingenol-b-on-the-suppressive-capacity-of-elite-suppressor-hiv-specific-cd8-t-cells
#7
Abena K Kwaa, Kennedy Goldsborough, Victoria E Walker-Sperling, Luiz F Pianowski, Lucio Gama, Joel N Blankson
BACKGROUND: Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28392275/exploring-the-influence-of-indololactone-structure-on-selectivity-for-binding-to-the-c1-domains-of-pkc%C3%AE-pkc%C3%AE%C2%B5-and-rasgrp
#8
Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E Lewin, Lia C Garcia, Christopher C Lai, James A Kelley, Megan L Peach, Peter M Blumberg, María J Comin
C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins...
March 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28272610/some-limitations-of-an-approach-to-the-assembly-of-bryostatins-by-ring-closing-metathesis
#9
Raphaël Dumeunier, Thomas Gregson, Somhairle MacCormick, Hiroki Omori, Eric J Thomas
Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27 fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28271111/syntheses-of-c17-c27-fragments-of-20-deoxybryostatins-for-assembly-using-julia-and-metathesis-reactions
#10
Matthew Ball, Thomas Gregson, Hiroki Omori, Eric J Thomas
Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28178410/strategies-to-extend-thrombolytic-time-window-for-ischemic-stroke-treatment-an-unmet-clinical-need
#11
REVIEW
Ike Dela Peña, Cesar Borlongan, Guofang Shen, Willie Davis
To date, reperfusion with tissue plasminogen activator (tPA) remains the gold standard treatment for ischemic stroke. However, when tPA is given beyond 4.5 hours of stroke onset, deleterious effects of the drug ensue, especially, hemorrhagic transformation (HT), which causes the most significant morbidity and mortality in stroke patients. An important clinical problem at hand is to develop strategies that will enhance the therapeutic time window for tPA therapy and reduce the adverse effects (especially HT) of delayed tPA treatment...
January 2017: Journal of Stroke
https://www.readbyqxmd.com/read/28146052/expansion-of-t-cells-with-interleukin-21-for-adoptive-immunotherapy-of-murine-mammary-carcinoma
#12
Christine K Zoon, Wen Wan, Laura Graham, Harry D Bear
We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect. DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21...
January 29, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27994072/hiv-1-latency-reversing-agents-prostratin-and-bryostatin-1-induce-blood-brain-barrier-disruption-inflammation-and-modulate-leukocyte-adhesion-transmigration
#13
Clélia Dental, Alizé Proust, Michel Ouellet, Corinne Barat, Michel J Tremblay
A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3...
December 19, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27993846/nonnucleoside-reverse-transcriptase-inhibitors-reduce-hiv-1-production-from-latently-infected-resting-cd4-t-cells-following-latency-reversal
#14
Jennifer M Zerbato, Gilda Tachedjian, Nicolas Sluis-Cremer
Therapeutic strategies that target the latent HIV-1 reservoir in resting CD4(+) T cells of infected individuals are always administered in the presence of combination antiretroviral therapy. Using a primary cell of HIV-1 latency, we evaluated whether different antiviral drug classes affected latency reversal (as assessed by extracellular virus production) by anti-CD3/CD28 monoclonal antibodies or bryostatin 1. We found that the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine significantly decreased HIV-1 production, by ≥1 log...
March 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27978828/integrin-fak-signaling-rapidly-and-potently-promotes-mitochondrial-function-through-stat3
#15
Nishant P Visavadiya, Matthew P Keasey, Vladislav Razskazovskiy, Kalpita Banerjee, Cuihong Jia, Chiharu Lovins, Gary L Wright, Theo Hagg
BACKGROUND: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. METHODS: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators...
December 15, 2016: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/27941949/in-vitro-effects-of-the-small-molecule-protein-kinase-c-agonists-on-hiv-latency-reactivation
#16
Jessica Brogdon, Widade Ziani, Xiaolei Wang, Ronald S Veazey, Huanbin Xu
The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27785754/nuclear-accumulation-of-histone-deacetylase-4-hdac4-exerts-neurotoxicity-in-models-of-parkinson-s-disease
#17
Qimei Wu, Xiaoyu Yang, Lei Zhang, Yu Zhang, Linyin Feng
Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson's disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP(+)/MPTP in vitro and in vivo...
October 26, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27714213/the-evolution-of-a-stereoselective-synthesis-of-the-c1-c16-fragment-of-bryostatins
#18
Matthew Ball, Anne Baron, Ben Bradshaw, Raphaël Dumeunier, Matthew O'Brien, Eric J Thomas
The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is described. Following early work using Stille reactions to prepare precursors for oxy-Michael reactions, a more efficient route was devised based on a ketophosphonate-aldehyde condensation to prepare the key dienone. Synthesis of the aldehyde required for the ketophosphonate condensation involved the highly stereoselective addition of a diorganocuprate derived from allylmagnesium bromide and copper(i) iodide to the methyl 5-hydroxyhex-2-ynoate prepared by ring-opening of a protected glycidol using lithiated methyl propiolate...
October 12, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27713589/replacement-of-the-bryostatin-a-and-b-pyran-rings-with-phenyl-rings-leads-to-loss-of-high-affinity-binding-with-pkc
#19
Mark E Petersen, Noemi Kedei, Nancy E Lewin, Peter M Blumberg, Gary E Keck
We describe a convergent synthesis of a bryostatin analogue in which the natural A- and B-ring pyrans have been replaced by phenyl rings. The new analogue exhibited PMA like behavior in cell assays, but failed to maintain high affinity binding for PKC, despite retaining an unaltered C-ring 'binding domain'.
October 19, 2016: Tetrahedron Letters
https://www.readbyqxmd.com/read/27676096/evaluation-of-chromane-based-bryostatin-analogues-prepared-via-hydrogen-mediated-c-c-bond-formation-potency-does-not-confer-bryostatin-like-biology
#20
John M Ketcham, Ivan Volchkov, Te-Yu Chen, Peter M Blumberg, Noemi Kedei, Nancy E Lewin, Michael J Krische
The synthesis and biological evaluation of chromane-containing bryostatin analogues WN-2-WN-7 and the previously reported salicylate-based analogue WN-8 are described. Analogues WN-2-WN-7 are prepared through convergent assembly of the chromane-containing fragment B-I with the "binding domain" fragment A-I or its C26-des-methyl congener, fragment A-II. The synthesis of fragment B-I features enantioselective double C-H allylation of 1,3-propanediol to form the C2-symmetric diol 3 and Heck cyclization of bromo-diene 5 to form the chromane core...
October 12, 2016: Journal of the American Chemical Society
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