Pharmacokinetic and pharmacodynamic properties of gs-9620, a novel toll-like receptor 7 agonist, demonstrate interferon-stimulated gene induction without detectable serum interferon at low oral dosess
Zheng J.,Drug Metabolism |
Pflanz S.,Biology |
Frey C.R.,Biology |
Hesselgesser J.,Clinical Virology and Medicinal Chemistry |
And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014
GS-9620 [8-(3-(pyrrolidin-1-ylmethyl)benzyl)-4-amino-2-butoxy-7,8- dihydropteridin-6(5H)-one] is a potent, orally bioavailable small-molecule agonist of Toll-like receptor 7 (TLR7) developed for finite treatment of chronic hepatitis B viral (HBV) infection, with the goal of inducing a liver-targeted antiviral effect without inducing the adverse effects associated with current systemic interferon-a (IFN-a) therapies. We characterized the pharmacodynamic response of GS-9620 in CD-1 mice and cynomolgus monkeys following intravenous or oral administration and showed that GS-9620 induces the production of select chemokines and cytokines, including IFN-a and interferon-stimulated genes (ISGs). It is noteworthy that we also demonstrated that, in animals and healthy human volunteers, oral administration of GS-9620 can induce a type I interferon-dependent antiviral innate immune response, as measured by whole-blood mRNA of the ISGs 2959-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-a, i.e., a presystemic response. Additionally, presystemic induction of hepatic OAS1 and MX1 mRNA was observed in CD-1 mice in the absence of detectable systemic IFN-a. We propose that the mechanism of this presystemic response is likely its high intestinal absorption,which facilitates localized activation of TLR7, probably in plasmacytoid dendritic cells at the level of gut-associated lymphoid tissue and/or the liver. This localized response is further supported by data that indicate onlyminimal contributions of systemic immune stimulation to the overall pharmacodynamic response to orally administered GS-9620. These data demonstrate that GS-9620 can induce an antiviral innate immune response without inducing a systemic IFN-a response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Chimia | Year: 2014
Winning in the global market place with brilliant innovations is the recipe for success for the Swiss economy. Indeed, Switzerland always stands out in the global rankings when it comes to innovation. Yet there is nothing as dangerous as to rest on one's laurels, and this is particularly true for R&D-based businesses. For this reason CTI, the Commission for Technology and Innovation, offers Swiss companies quick and effective access to knowledge available at Swiss public research institutions, and to international R&D programs promoting application-oriented research. Knowledge and technology transfer are promoted - via its KTT support - through National Thematic Networks (NTNs), Innovation Mentors and information platforms. The following article highlights the activities of the National Thematic Networks and invites Swiss companies and research institutes to benefit from the multiple offers and services available. © Schweizerische Chemische Gesellschaft.
Prates J.,São Paulo State University |
Franco-Salla G.B.,São Paulo State University |
Dinarte dos Santos A.R.,University of Sao Paulo |
da Silva W.A.,University of Sao Paulo |
And 4 more authors.
Gene | Year: 2015
Cervical cancer is the second most frequent cancer in women worldwide and is associated with genetic alterations, infection with human papilloma virus (HPV), angiogenesis and inflammatory processes. The idea that inflammation is involved in tumorigenesis is supported by the frequent appearance of cancer in areas of chronic inflammation. On the other hand, the inflammatory response is controlled by the action of anti-inflammatory mediators, among these mediators, annexin A1 (ANXA1), a 37. kDa protein was detected as a modulator of inflammatory processes and is expressed by tumor cells.The study was carried out on the epithelial cancer cell line (SiHa) treated with the peptide of annexin A1 (ANXA1Ac2-26). We combined subtraction hybridization approach, Ingenuity Systems software and quantitative PCR, in order to evaluate gene expression influenced by ANXA1.We observed that ANXA1Ac2-26 inhibited proliferation in SiHa cells after 72h. In these cells, 55 genes exhibited changes in expression levels in response to peptide treatment. Six genes were selected and the expression results of 5 up-regulated genes (TPT1, LDHA, NCOA3, HIF1A, RAB13) and one down-regulated gene (ID1) were research by real time quantitative PCR. Four more genes (BMP4, BMPR1B, SMAD1 and SMAD4) of the ID1 pathway were investigated and only one (BMPR1B) shows the same down regulation.The data indicate the involvement of ANXA1Ac2-26 in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of cervical cancer. © 2015 Elsevier B.V.
Atamanyuk D.,Medicinal Chemistry |
Faivre F.,Medicinal Chemistry |
Oxoby M.,Medicinal Chemistry |
Ledoussal B.,Medicinal Chemistry |
And 3 more authors.
Journal of Medicinal Chemistry | Year: 2013
In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their Gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies. © 2013 American Chemical Society.
Byington C.L.,University of Utah |
Ampofo K.,University of Utah |
Stockmann C.,University of Utah |
Adler F.R.,Biology |
And 7 more authors.
Clinical Infectious Diseases | Year: 2015
Background. This study: (1) describes the viral etiology of respiratory illness by prospectively collecting weekly symptom diaries and nasal swabs from families for 1 year, (2) analyzed data by reported symptoms, virus, age, and family composition, and (3) evaluated the duration of virus detection. Methods. Twenty-six households (108 individuals) provided concurrent symptom and nasal swab data for 4166 person-weeks. The FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC) was used to detect 16 respiratory viruses. Viral illnesses were defined as ?1 consecutive weeks with the same virus detected with symptoms reported in ?1 week. Results. Participants reported symptoms in 23% and a virus was detected in 26% of person-weeks. Children younger than 5 years reported symptoms more often and were more likely to have a virus detected than older participants (odds ratio [OR] 2.47, 95% confidence interval [CI], 2.08-2.94 and OR 3.96, 95% CI, 3.35-4.70, respectively). Compared with single person households, individuals living with children experienced 3 additional weeks of virus detection. There were 783 viral detection episodes; 440 (56%) associated with symptoms. Coronaviruses, human metapneumovirus, and influenza A detections were usually symptomatic; bocavirus and rhinovirus detections were often asymptomatic. The mean duration of PCR detection was ≤2 weeks for all viruses and detections of ?3 weeks occurred in 16% of episodes. Younger children had longer durations of PCR detection. Conclusions. Viral detection is often asymptomatic and occasionally prolonged, especially for bocavirus and rhinovirus. In clinical settings, the interpretation of positive PCR tests, particularly in young children and those who live with them, may be confounded. © The Author 2015.
Gerusz V.,Medicinal Chemistry |
Denis A.,Medicinal Chemistry |
Denis A.,Glaxosmithkline |
Faivre F.,Medicinal Chemistry |
And 23 more authors.
Journal of Medicinal Chemistry | Year: 2012
In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials. © 2012 American Chemical Society.
Desroy N.,Medicinal Chemistry |
Desroy N.,Galapagos |
Denis A.,Medicinal Chemistry |
Denis A.,Glaxosmithkline |
And 18 more authors.
Journal of Medicinal Chemistry | Year: 2013
We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors. © 2013 American Chemical Society.
PubMed | Health Science University, Biology, University of Colorado at Denver, University of Louisville and 7 more.
Type: | Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | Year: 2016
Hispanic women have lower breast cancer incidence rates than non-Hispanic white (NHW) women. To what extent genetic versus non-genetic factors account for this difference is unknown.Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2326 Hispanic and 1854 NHW postmenopausal women from the US and Mexico in the Breast Cancer Health Disparities Study.The inverse association between % Native American(NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio(OR)=1.39, 95% confidence interval(CI)=1.00-1.92 among US Hispanics; OR=1.92 (1.29-2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher BMI was associated with reduced risk among women with lower NA ancestry only [BMI <25 versus >30: OR=0.65 (0.44-0.98) among US Hispanics; OR=0.53 (0.29-0.97) among Mexicans]. The average number of risk factors among cases was inversely related to % NA ancestry.The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. While the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry.These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry.
PubMed | Georgia Institute of Technology, Biology., Georgia State University, Center for Biotechnology and Drug Design and Vrije Universiteit Brussel
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2014
Nitronate monooxygenase (NMO) oxidizes the mitochondrial toxin propionate 3-nitronate (P3N) to malonate semialdehyde. The enzyme has been previously characterized biochemically in fungi, but no structural information is available. Based on amino acid similarity 4,985 genes are annotated in the GenBank(TM) as NMO. Of these, 4,424 (i.e. 89%) are bacterial genes, including several Pseudomonads that have been shown to use P3N as growth substrate. Here, we have cloned and expressed the gene pa4202 of Pseudomonas aeruginosa PAO1, purified the resulting protein, and characterized it. The enzyme is active on P3N and other alkyl nitronates, but cannot oxidize nitroalkanes. P3N is the best substrate at pH 7.5 and atmospheric oxygen with k(cat)(app)/K(m)(app) of 12 10(6) M(-1) s(-1), k(cat)(app) of 1300 s(-1), and K(m)(app) of 110 m. Anerobic reduction of the enzyme with P3N yields a flavosemiquinone, which is formed within 7.5 ms, consistent with this species being a catalytic intermediate. Absorption spectroscopy, mass spectrometry, and x-ray crystallography demonstrate a tightly, non-covalently bound FMN in the active site of the enzyme. Thus, PA4202 is the first NMO identified and characterized in bacteria. The x-ray crystal structure of the enzyme was solved at 1.44 , showing a TIM barrel-fold. Four motifs in common with the biochemically characterized NMO from Cyberlindnera saturnus are identified in the structure of bacterial NMO, defining Class I NMO, which includes bacterial, fungal, and two animal NMOs. Notably, the only other NMO from Neurospora crassa for which biochemical evidence is available lacks the four motifs, defining Class II NMO.
PubMed | Biology., Curriculum in Genetics and Molecular Biology and., Curriculum in Genetics and Molecular Biology and email@example.com., Gunma University and 2 more.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Germ cells are maintained in a pristine non-aging state as they proliferate over generations. Here, we show that a novel function of the Caenorhabditis elegans RNA interference proteins RNAi spreading defective (RSD)-2 and RSD-6 is to promote germ cell immortality at high temperature. rsd mutants cultured at high temperatures became progressively sterile and displayed loss of small interfering RNAs (siRNAs) that target spermatogenesis genes, simple repeats, and transposons. Desilencing of spermatogenesis genes occurred in late-generation rsd mutants, although defective spermatogenesis was insufficient to explain the majority of sterility. Increased expression of repetitive loci occurred in both germ and somatic cells of late-generation rsd mutant adults, suggesting that desilencing of many heterochromatic segments of the genome contributes to sterility. Nuclear RNAi defective (NRDE)-2 promotes nuclear silencing in response to exogenous double-stranded RNA, and our data imply that RSD-2, RSD-6, and NRDE-2 function in a common transgenerational nuclear silencing pathway that responds to endogenous siRNAs. We propose that RSD-2 and RSD-6 promote germ cell immortality at stressful temperatures by maintaining transgenerational epigenetic inheritance of endogenous siRNA populations that promote genome silencing.