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STONY BROOK, NY, United States

Wang H.,State University of New York at Stony Brook | Liu L.,State University of New York at Stony Brook | Liu L.,Stony Brook Biotechnology | Lu Y.,State University of New York at Stony Brook | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24. min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography. © 2015 Elsevier Ltd. Source


Wang H.,State University of New York at Stony Brook | Lu Y.,State University of New York at Stony Brook | Lu Y.,Stony Brook Biotechnology | Liu L.,State University of New York at Stony Brook | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a Ki value of 0.01 nM and a residence time of 750 min on the enzyme target, has been evaluated in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU's in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ∼1/41 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo. © 2014 Elsevier Masson SAS. Source


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant The goal of this Phase I is to develop a prototype for a novel antiviral therapy directed towards Epstein Barr virus based on a novel post transcriptional regulatory mechanism called structurally interacting RNA or sxRNA We are pioneering a revolutionary antiviral approach that uses a viral encoded microRNA miRNA to create specificity even in infections in their latent stage This transient mRNA therapeutic will make it possible to specifically express a protein of interest only in virus infected cells by exploiting post transcriptional regulation of a transgene triggered by the unique miRNA profile of a virus infected cell We have developed a trans RNA switching mechanism called structurally interacting RNA or andquot sxRNAandquot for short that relies on the unique expression of a microRNA to turn andquot onandquot and andquot offandquot the expression of an ectopic gene of choice Certain RNA binding proteins RBPs when bound to mRNA increase translation by several orders of magnitude We have shown that it is possible to create a andquot switchandquot within an mRNA such that a trans interaction with an endogenous miRNA can ablate or stabilize an RBP binding site By coupling this post transcriptional gene regulation with the microRNA signature patterns in cell types sxRNA technology can enable cell specific expression of a desired protein or reporter gene to positively or negatively select for a tissue type disease state or developmental stage sxRNA technology represents a revolutionary way to regulate transient gene expression based on the unique miRNA profile in a cell We propose to develop a novel sxRNA based anti viral directed against Epstein Barr virus EBV an oncovirus In addition to causing infectious mononucleosis EBV is associated with cancers of B cells e g immunocompromised associated B cell lymphomas including Burkitt and Hodgkin lymphomas and epithelial cells e g nasopharyngeal cell carcinoma gastric carcinoma and breast cancer A therapeutic that targets both lytic and latent EBV would make a significant impact on human health and lead to similar therapeutics to other members of the Herpesvirus family PUBLIC HEALTH RELEVANCE The goal of this Phase I is to develop a prototype for a novel antiviral therapy directed towards Epstein Barr virus based on a novel post transcriptional regulatory mechanism called structurally interacting RNA or sxRNA EBV is associated with cancers of B cells e g immunocompromised associated B cell lymphomas including Burkitt and Hodgkin lymphomas and epithelial cells e g nasopharyngeal cell carcinoma gastric carcinoma and breast cancer A therapeutic that targets EBV both lytic and latent EBV would make a significant impact on human health and lead to similar therapeutics to other members of the Herpesvirus family


Wang H.,State University of New York at Stony Brook | Lu Y.,State University of New York at Stony Brook | Liu L.,Stony Brook Biotechnology | Kim S.W.,Brookhaven National Laboratory | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a K i value of 0.01 nM and a residence time of 750 min on the enzyme target, has been evaluated in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU's in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ∼1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo. © 2014 Elsevier Masson SAS. Source


Huang E.,State University of New York at Stony Brook | Zhu W.,State University of New York at Stony Brook | Dhundale A.,State University of New York at Stony Brook | Dhundale A.,Stony Brook Biotechnology | And 4 more authors.
Thrombosis and Haemostasis | Year: 2013

The platelet transcriptome has been extensively characterised using distinct genetic profiling platforms, with evolving evidence for differential expression patterns between healthy individuals and subject cohorts with various haematologic and cardiovascular disorders. Traditional technological platforms for platelet genetic biomarker quantification have limited applicability for clinical molecular diagnostics due to inherent complexities related to RNA isolation and analysis. We have previously established the feasibility of fluorescent microspheres as a simple and reproducible strategy for simultaneous quantification of platelet mRNAs from small volume of blood using intact platelets. We now extend these observations by formally comparing in a 50-member normal cohort the cross-platform behaviour of fluorescent microspheres to the currently accepted Q-PCR standard, using a clinically relevant 15-biomarker gene subset able to discriminate among normal and thrombocytosis cohorts. When compared to Q-PCR, genetic biomarker quantification using fluorescent microspheres demonstrated lower coefficients of variation for low-abundant transcripts, better linearity in serially diluted samples, and good overall betweenplatform consistency via the geometric mean regression. Neither platform demonstrated age or gender effects for any of the 15 biomarkers studied. Binding site saturation for highly abundant transcripts using fluorescent microspheres can be readily eliminated using an optimal platelet number corresponding to 0.3 ml of peripheral blood, additionally applicable to thrombocytopenic cohorts. These data provide a detailed cross-platform analysis using a relevant biomarker subset, further highlighting the applicability of fluorescent microspheres as potentially superior to Q-PCR for platelet mRNA diagnostics. © Schattauer 2013. Source

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