Stony Brook Biotechnology

STONY BROOK, NY, United States

Stony Brook Biotechnology

STONY BROOK, NY, United States
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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.


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.


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.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 205.71K | Year: 2015

DESCRIPTION provided by applicant Traverse Biosciences Inc is a pre clinical stage drug development company working to commercialize new chemical entities which act to resolve inflammatory conditions through pleiotropic host modulation of pathologically unrestrained matrix metalloproteinases MMPs and pro inflammatory cytokines The companyandapos s lead drug candidate TRB N is a proprietary chemically modified curcumin developed by the co inventor of Periostat R and Oracea R currently the only FDA approved MMP inhibitors Periodontal disease is a chronic inflammatory condition involving interactions between oral bacterial products numerous cell populations in the host tissues and inflammatory mediators such as cytokines chemokines arachidonic acid metabolites and proteolytic enzymes including matrix metalloproteinases which collectively contribute to tissue destruction and bone resorption The Centers for Disease Control CDC estimates that the prevalence of periodontitis in U S adults aged years and older is M and the prevalence of mild moderate and severe periodontitis is M M and M respectively Periodontal disease has also been associated with other chronic conditions such as heart disease diabetes and various cancers Most current drug therapies are primarily focused on the management of the microbial biofilm not taking into account the central role of inflammation in causing tissue damage which makes this therapy only partly effective TRB N exhibits pleiotropic anti inflammatory effects as a broad spectrum MMP modulator as well as an inhibitor of pro inflammatory cytokines such as IL b TNF a and IL likely through interruption of the NF kB pathway TRB N acts to resolve inflammation via a multi target host modulatory approach that overcomes the challenges of redundancy compensation and necessity exhibited by the immune system Curcumin was chosen as a parent structure because it also has a diketo moiety similar to that of the tetracyclines and chemical modifications were pursued to overcome limited clinical use of curcumin due to its insolubility rapid metabolism and modest biological activity Our long term goal is to develop an effective inhibitor of inducible MMPs with minimal side effects and toxicity that will significantly reduce the complications associated with periodontal disease The objective here which is the next step in the pursuit of our goal is to test the efficacy of our lead compound TRB N in a LPS induced rat model of periodontal disease Our Phase I Hypothesis is that administration of TRB N will protect alveolar bone from MMP damage in a LPS induced rat model of periodontal disease and lower the gingival tissue and serum levels of pro inflammatory mediators Our specific aims are to evaluate the effectiveness of our lead compound TRB N to prevent and treat periodontal disease using a LPS induced rat model Bone loss will be determined by measuring the distance from a fixed anatomical landmark the cemento enamel junction to the alveolar bone crest and levels activity of MMPs and inflammatory cytokines will also be assessed Successful completion of Phase I will allow us to pursue Phase II funding to support pre clinical testing of TRB N utilizing a clinically applicable canine model of periodontal disease We hope to commercialize TRB N as an FDA approved pharmaceutical intervention for the treatment of periodontal disease in an orally administer i e systemic formulation and intend to pursue pre clinical and clinical development to demonstrate the safety and efficacy of this lead drug candidate PUBLIC HEALTH RELEVANCE The Centers for Disease Control CDC estimates that the prevalence of periodontitis in U S adults aged years and older is M and the prevalence of mild moderate and severe periodontitis is M M and M respectively Periodontal disease has also been associated with other chronic conditions such as heart disease diabetes and various cancers This proposed project is directly relevant to the public health since it is to develop a promising new drug candidate for the treatment of this critical unmet medical need Moreover the drug candidate has also shown promise in a variety of other disease areas related to chronic inflammation demonstrating the potential for broad application and societal benefit if proven to be both safe and effective


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 | 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.

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