Artigo Revisado por pares

Patent Highlights

2015; Future Science Ltd; Volume: 4; Issue: 1 Linguagem: Inglês

10.4155/ppa.14.50

ISSN

2046-8962

Autores

Hermann AM Mucke,

Tópico(s)

Epigenetics and DNA Methylation

Resumo

Pharmaceutical Patent AnalystVol. 4, No. 1 Patent HighlightsFree AccessPatent HighlightsHermann AM MuckeHermann AM MuckeHM Pharma Consultancy E-mail Address: h.mucke@hmpharmacon.comPublished Online:7 Jan 2015https://doi.org/10.4155/ppa.14.50AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail AbstractA snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.Keywords: obesityserotonintryptophan hydroxylaseApproximately 95% of the serotonin in the human body is in the periphery, where Tph1 catalyzes the rate-limiting step of its synthesis from dietary tryptophan. According to this invention, reduction of peripheral serotonin levels by inhibition of Tph1 (preferably by LP-533401 and LP-615819, two very closely related [pyrimidin-4-yl][phenyl]propanoic acid derivatives [1]) can modify the energy balance towards leanness. TPH1-knockout mice, which have very low levels of circulating serotonin (but maintain normal levels of serotonin in the brain due to the sustained presence of the Tph2 isoenzyme, which controls central serotonin production [2]), are shown to be protected against obesity, chronic low-grade inflammation, fatty liver and insulin resistance. Tph1 inhibition increases thermogenic energy expenditure by enhancing brown adipose tissue metabolic activity, as shown by oxygen consumption and tissue fluorodeoxyglucose uptake. Weight loss in obese people can increase serotonin and dopamine blood levels; subjects with higher serotonin concentrations after the weight loss intervention showed lower energy intake during the intervention [3].Published 21 August 2014Keywords: lymphatic vesselspolycystic kidney diseasesvascular endothelial growth factor CPolycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases, and PKD1 is the most frequently mutated gene in the autosomal-dominant variant of the condition. In mice, its loss disrupts morphogenesis of the subcutaneous lymphatic network, with lymphatic endothelial cells displaying defective polarity, elongation and adherens junctions [4]. The inventors have demonstrated that the microvasculature surrounding the kidney cysts shifts from a blood to a lymphatic endothelial phenotype in PKD, and that treatment with VEGF-C (a potent inducer of lymphangiogenesis [5]) significantly reduced cyst formation and enhanced growth, survival and migration of lymphatics in a mouse model of PKD. This contrasts with the earlier suggestion that VEGFR1 and 2 inhibition may block cyst growth [6]; however, VEGF-C acts preferentially on VEGFR3. VEGF-C (and VEGF-D) variants suitable for use in the invention are described in WO/2008/096268. Data obtained with congenital polycystic kidney and Pkd1-knockout mice are presented; VEGF-C-treated animals had approximately half the kidney size and average cyst size compared with their untreated peers.Published 21 August 2014Keywords: antibacterial agentsfucosenorovirusoligosaccharidesrotavirusNoroviruses (nonenveloped caliciviruses) are the most common cause of viral acute gastroenteritis and one of the most common causes of death worldwide for children under the age of 3 years. Histo–blood groups antigens (complex oligosaccharides that are expressed on mucosal surfaces and erythrocyte membranes) serve as receptors for noroviruses [7]. At present, neither a vaccine nor a causal therapy is available. Building on an earlier observation that fucosylated oligosaccharides are the agents that protect breast-fed infants against viral diarrhea [8], the inventor has designed such synthetic or recombinant oligosaccharides comprising a nonreducing end and a reducing end. The reducing end consists of a galactose linked via a β(1–4)-glycosidic bond to a glucose; the nonreducing end comprises a second carbohydrate unit linked via a β(1–3)-glycosidic bond to the first carbohydrate unit of the reducing end, and wherein the second carbohydrate unit comprises at least one fucose and a galactose and at least one N-acetylglucosamine or N-acetylgalactosamine. The idea is that these oligosaccharides form complexes with noroviruses and rotaviruses and/or their histo–blood groups antigen receptors; in either case. virus binding – the first key step in infection – is blocked. No supporting data are presented (for the companion peer-reviewed paper, see [9]). The application cites WO/2005/055944, which discloses 2-fucosyllactose linked to human serum albumin for the treatment of infections, as prior art; the examiner cites several more, including Abbott's WO/2012/092153.Published 28 August 2014Keywords: diabetes mellitushumaninsulin-secreting cellsregenerative medicineSERPINB1 proteinReduced functional β-cell mass is a central feature in both forms of diabetes, and regenerating β-cells (instead of merely stimulating the remaining ones to release more insulin) remains the goal of a curative therapy for diabetes. The inventors used liver-specific insulin receptor-knockout mice [10], which exhibit dramatic islet hyperplasia, to demonstrate that humoral, non-neural, non-cell-autonomous factor(s) induce β-cell proliferation in these animals. In mouse and human β-cell ex vivo proliferation assays, the most likely candidate is SerpinB1 (a 42-kDa protein known to regulate neutrophil elastase, cathepsin G, chymase, chymotrypsin and kallikrein-3); it acts independent of ambient glucose and insulin levels. A direct effect of SerpinB1 and its pharmacological mimetics, sivelestat and GW-311616A, on the promotion of β-cell proliferation in vivo and in vitro occurred in a dose-dependent manner. Circulating levels of SerpinB1 were elevated in liver-specific insulin receptor-knockout mice sera. These findings are not totally surprising; it is known that SerpinB1 activity correlates with β-cell proliferation induced by exendin-4 or during regeneration after partial pancreatectomy [11]. Sivelastat is the agent in Ono Pharmaceuticals' Elaspol®, approved in 2002 in Japan (and subsequently other countries) for acute lung injury associated with systemic inflammatory response syndrome [12]. Substantial redevelopment would be required if it were to be used in diabetes.Published 28 August 2014Keywords: amniotic fluidcomplement C1 inactivator proteinsembolismhumanSERPING1 proteinuterine hemorrhageAmniotic fluid embolism (AFE) is a rare and often undiagnosed cause of acute pulmonary hypertension in pregnancy and uncontrollable postpartum uterine hemorrhage, precipitated by an ingression of amniotic fluid into maternal blood [13,14]. While decreased levels of complement components C3 and C4 have been reported in AFE patients who subsequently develop disseminated intravascular coagulation, an involvement of C1 in AFE had not been described. Data from the AFE registry at Hamamatsu University School of Medicine (Japan) showed that serum levels of C1 esterase inhibitor (the only known physiological inhibitor of of C1s and C1r, the activated homologous serine protease forms of C1, and also a major regulator of the kallikrein–kinin system) were 53 ± 21.0% in the control group and 35.5 ± 13.5% in the AFE risk group (p < 0.01). The inventors considered that overactivation of the maternal complement system causes excessive consumption of C1 inhibitor. One emergency department case report is presented where CSL Behring's C1 inhibitor product, Berinert®, was successfully used to stop postpartum bleeding (for the companion peer-reviewed paper, see [15]).Published 4 September 2014Keywords: bacteriadyphyllineFlhB proteinSalmonellatrimethoprimMany Gram-negative pathogens use type III secretion systems (T3SSs), flagellar multiprotein export apparatuses that transport effectors into the cytoplasm of the host cell. A T3SS consists of a basal body anchored in the bacterial membrane that develops an external filament that punches a pore into the plasma membrane of its target and has been described as a nanosyringe or injectosome. The T3SS switches substrate specificity once the filament has reached an appropriate length. In Salmonella, this tightly regulated switch is controlled by two proteins, FliK and FlhB [16]. The C-terminal cytoplasmic domain of FlhB (FlhBc) undergoes autocatalytic cleavage, which is essential for the switching process [17]. The most important finding of the invention is that flexibility of the large nonconserved loop in the globular domain of FlhBc is required for the entire T3SS to function. Considering the similarity between the flagellar and needle proteins, this loop could be a promising antibacterial drug target. The most effective small-molecule ligands that were identified among 237 candidates were dyphylline (a theophylline derivative that was used as a brochodilator but is also known to improve the antibacterial effect of oxidizing agents) and trimethoprim (a pyrimidine inhibitor of dihydrofolate reductase). This serves to shed additional light on the mechanisms of both of these old compounds, but could also open new chemical spaces not previously investigated in this context. The screening method that has been developed should be useful (for companion peer-reviewed papers, see [18,19]).Published 4 September 2014Keywords: adoptive immunotherapycancerIkaros transcription factorTreating melanoma [20] and certain leukemias [21] with allogeneic T cells that are extracorporeally expanded and primed against the tumors has shown remarkable successes. However, there are substantial efficacy limitations, especially with the most common solid tumors. In many instances, T cells that enter cancerous tissue are rapidly inactivated, probably by secreted immune-inhibitory factors or by interactions with inhibitory leukocytes and/or contact with inhibitory molecules on the surface of tumor cells. The inventors have discovered that inhibition of expression or activity of Ikaros, a zinc finger DNA binding protein and transcriptional repressor that silences IL-2 in anergic CD4+ T cells and restricts autocrine IL-2 production by CD8+ T cells [22], enhances the cytolytic activity of T cells. The modified T cells may be haploinsufficient for Ikaros, may express a dominant negative Ikaros lacking the DNA binding domain or may produce increased levels of at least one lytic mediator (IFN-γ, TNF-α or granzyme B). Preferably, the Ikaros inibitor is an interfering RNA. The approach is suitable for therapies in which T cells are modified to express a desired protein (e.g., a chimeric antigen receptor [CAR]). At a ratio of 40 T cells to one tumor cell, Ikaros-unmodified T cells expressing a mesothelin CAR killed approximately 10% of the tumor cells, while CAR T cells from knockout mice lacking one copy of Ikaros eliminated approximately 40% of tumor cells. Of significant relevance is the fact that lenalidomide reduces Ikaros in human T cells bearing antimesothelin CAR and increases their cytokine production.Published 12 September 2014Keywords: γ-synucleinendometriosisgynecologyParkinson's disease, dementia with Lewy bodies and multiple system atrophy are α-synucleinopathies and sometimes show the involvement of γ-synuclein, an isoform that is first and foremost a cytoplasmic oncogene and an unfavorable biomarker for multiple types of cancer [23]. However, this does not seem to apply to survival in endometrioid carcinoma [24], which is associated with endometriosis – a relatively frequent condition caused by estrogen-dependent extrauterine growth of endometrial cells that have escaped into the peritoneal cavity. The inventor had observed earlier that levels of γ-synuclein were significantly higher in ectopic (extrauterine) than in eutopic (normal, uterine) endometrial tissue samples [25]. Considering the numerous roles of γ-synuclein in activating inflammatory mediators, kinases and matrix metalloproteases, it was probably only a small step to claim γ-synuclein inhibitors (preferably the peptide ST011 with the amino acid sequence GNSALHVASQHG, which contains an ankyrin repeat-like motif and was claimed for the treatment of cancer in WO/2007/098611) for the treatment of endometriosis. Direct in vivo binding of a ST011–TAT hybrid peptide to its intracellular target was demonstrated in coimmunoprecipitation experiments. In a mouse model of estrogen-induced endometriosis, it significantly reduced the size of peritoneal lesions.Published 18 September 2014Keywords: cancerepigenesisgeneticglycogen storage diseaseprotein arginine N-methyltransferasesCARM1 is one of the enzymes that modulates epigenetic regulation of gene expression through methylation of arginine residues in histones. It is involved in cellular development, differentiation, senescence, malignant transformation and apoptosis [26]. Over 30 arginine methylation sites have been identified on core histones; these modifications alter protein structure, impact interactions with DNA and also generate docking sites for effector molecules [27]. Small-molecule enhancers [28] as well as inhibitors [29] of CARM1 have been reported. The novel CARM1 inhibitors presented here are mostly structured around an imidazopyridinyl, pyrazolopyridinyl, pyrrolopyrimidinyl or pyrazolotriazinyl core moiety. IC50 values were determined for 66 chemically identified compounds and are said to be mostly in the submicromolar range, but are disclosed only in a categorical fashion. Corresponding to the involvement of CARM1 overactivation on so many levels, the claims span the range of cancers to skeletal muscle metabolic disorders. It is difficult to predict whether inhibition of CARM1 can ever be practical, even if it is selective over other members of the PRMT family, which may have alternative isoforms of currently unrecognized functions. Utility as a third-line therapy of common solid tumors probably is the best opportunity (also see Epizyme's WO/2014/153090 claiming pyrazoles as PRMT1 inhibitors).Published 18 September 2014Keywords: apoptosis regulatory proteinsBAG3 proteincancerhumanBAG3 is a 74-kDa cytoplasmic co-chaperonin that interacts with the ATPase domain of HSP70 through the domain defined by its amino acids 110–124 (the BAG domain). BAG3 also contains conserved motifs that can mediate binding to other proteins. In normal cells, its expression is inducible by the typical stressors and it is part of the standard stress response. In transformed cells, it is constitutively expressed and protects cancer cells against apoptosis by modulating the NF-κB pathway [30] or by preventing Bax translocation to mitochondria [31]. In pancreatic adenocarcinoma cell lines, silencing BAG3 gene expression with siRNAs induces cell death and decreases resistance to gemcitabine [32]. The inventors have demonstrated that monoclonal antibody inhibition of extracellular BAG3 also impairs the development of pancreatic tumor cells. Monoclonal antibodies were raised against four BAG3-specific peptides (DRDPLPPGWEIKIDPQ, SSPKSVATEERAAPS, DKGKKNAGNAEDPHT and NPSSMTDTPGNPAAP). Nude female BALB/c mice pancreatically inoculated with pancreatic adenocarcinoma cells showed over 75% tumor growth reduction in situ, and over 45% considering the area surrounding the tumor, when treated with the anti-BAG3 monoclonal antibodies. This suggests that tumor dissemination was also inhibited. The fact that depleting or neutralizing free BAG3 also serves a therapeutic purpose could offer a new perspective for cancer treatment; however, blocking BAG3 in the brain might be problematic, because it is involved in the removal of tau protein from neurons [33].Published 25 September 2014Keywords: advanced glycosylation endproductsdiabetes mellitusglyoxalMaillard reactionThis invention relates to compounds acting in the GI tract to eliminate dietary dicarbonyls, which could undergo a Maillard reaction (i.e., a nonenzymatic glycation reaction) with amino acid side chains of proteins to form advanced glycation end products (AGEs). Whether pre-existing dietary AGEs are absorbed in significant quantities and whether they are harmful if absorbed are questions under current debate [34,35]; however, the key role of in situ-generated AGEs in the development of diabetic complications is undisputed. The sequestrants of the invention contain amine groups separated by two, three or four carbons, and can be small molecules, but are preferably polymers such as epichlorohydrin-cross-linked poly(methyleneamine), poly(2,3-diamino[{3-[(2 -methyl-1-oxo-2-propen-1-yl)amino]propyl} amino]propaneamide-co-ethylene bis-methacrylamide) or poly(3,4-diaminostyrene-co-divinyl benzene). These polymers were able to bind up to 49 mg of methylglyoxal (the prototypical dicarbonyl AGE precursor) per gram of compound. Similar effects have been reported for two common dietary flavonoids – quercetin and phloretin [36] – and for several plant polysaccharides [37].Published 25 September 2014Keywords: cataractcrystallinspolyethylene glycolspresbyopiasuccinimidesCataracts are opacities in the lens of the eye caused by aggregations and chemical modifications of crystallins, which comprise approximately 90% of the lens proteins. During aging, the concentration of the soluble chaperone α-crystallin declines as it becomes incorporated into high-molecular-weight aggregates and insoluble protein. This makes the β- and γ-crystallins, which function primarily as structural proteins, more vulnerable to chemical damage [38]. While the β-crystallins form dimers as well as hetero- and homo-oligomers and exhibit a repulsive force in solution, the γ-crystallins are monomers in the eye and exhibit an attractive electrostatic interaction attributed to nonspecific protein or water interactions. The γ-crystallins, therefore, are most prone to aggregation when the chaperones are lost. Presbyopia, a benign and almost unavoidable hallmark of aging, involves no loss of lens tranparency but is otherwise related to cataract formation [39,40]. The invention discloses γ-crystallin charge-masking agents (excluding polypeptides, because these have been claimed by the University of Washington [WA, USA] in WO/2006/052821) intended to counter these processes. These are bifunctional molecules containing a leaving group (designed to interact with charged amino acid residues on γ-crystallin) covalently linked to a 'molecular bristle' (which provides distance between the γ-crystallin molecules and prevents aggregation). PEG functionalized with N-hydroxysuccinimide, maleinimide or biotin is among the preferred examples; PEGylation was chosen because this modification has been shown to increase the solubility of proteins without affecting their 3D structure or other essential properties. Data on agent transport across the epithelium of human cadaver eyes with cataracts are presented, along with their performance in terms of opacity reversal, which would be a true breakthrough if replicated in vivo. The agents can be formulated for delivery as eyedrops or through punctal plugs or hydrogel contact lenses (for the peer-review companion paper, see [41]).Published 25 September 2014Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Zhong H, Huang W, He G et al. 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Phys. 139(12), 121914 (2013).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 4, No. 1 Follow us on social media for the latest updates Metrics History Published online 7 January 2015 Published in print January 2015 Information© Future Science LtdKeywordsobesityserotonintryptophan hydroxylaselymphatic vesselspolycystic kidney diseasesvascular endothelial growth factor Cantibacterial agentsfucosenorovirusoligosaccharidesrotavirusdiabetes mellitushumaninsulin-secreting cellsregenerative medicineSERPINB1 proteinamniotic fluidcomplement C1 inactivator proteinsembolismhumanSERPING1 proteinuterine hemorrhagebacteriadyphyllineFlhB protein Salmonella trimethoprimadoptive immunotherapycancerIkaros transcription factorγ-synucleinendometriosisgynecologycancerepigenesisgeneticglycogen storage diseaseprotein arginine N-methyltransferasesapoptosis regulatory proteinsBAG3 proteincancerhumanadvanced glycosylation endproductsdiabetes mellitusglyoxalMaillard reactioncataractcrystallinspolyethylene glycolspresbyopiasuccinimidesPDF download

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