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Bozeman, MT, United States

Etoga J.-L.G.,University of Montana | Ahmed S.K.,University of Montana | Patel S.,University of Montana | Bridges R.J.,University of Montana | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A panel of amino acid analogs and conformationally-restricted amino acids bearing a sulfonic acid were synthesized and tested for their ability to preferentially inhibit the obligate cysteine-glutamate transporter system xc - versus the vesicular glutamate transporter (VGLUT). Several promising candidate molecules were identified: R/S-4-[4′-carboxyphenyl]-phenylglycine, a biphenyl substituted analog of 4-carboxyphenylglycine and 2-thiopheneglycine-5-sulfonic acid both of which reduced glutamate uptake at system xc - by 70-75% while having modest to no effect on glutamate uptake at VGLUT. © 2009 Elsevier Ltd. All rights reserved.


Bharate S.B.,University of Montana | Prins J.M.,University of Montana | George K.M.,University of Montana | Thompson C.M.,University of Montana | Thompson C.M.,Ateris Technologies, Llc
Journal of Agricultural and Food Chemistry | Year: 2010

The stability, hydrolysis, and uptake of the organophosphates methyl parathion and methyl paraoxon were investigated in SH-SY5Y cells. The stabilities of (14CH3O)2-methyl parathion (14C-MPS) and (14CH3O)2-methyl paraoxon (14C-MPO) at 1 μM in culture media had similar half-lives of 91.7 and 101.9 h, respectively. However, 100 μM MPO caused >95% cytotoxicity at 24 h, whereas 100 μM MPS caused 4-5% cytotoxicity at 24 h (∼60% cytotoxicity at 48 h). Greater radioactivity was detected inside cells treated with MPO as compared to MPS, although >80% of the total MPO uptake was primarily dimethyl phosphate (DMP). Maximum uptake was reached after 48 h of 14C-MPS or 14C-MPO exposure with total uptakes of 1.19 and 1.76 nM/106 cells for MPS and MPO, respectively. The amounts of MPS and MPO detected in the cytosol after 48 h of exposure time were 0.54 and 0.37 nM/106 cells, respectively. © 2010 American Chemical Society.


Ahmed S.K.,University of Montana | Etoga J.-L.G.,University of Montana | Patel S.A.,University of Montana | Bridges R.J.,University of Montana | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic α-amino group. To test this hypothesis, a series of analogs using a hydantoin (pKa ∼ 9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system xc-). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5 mM but few inhibited system xc- greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system xc- inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT. © 2011 Elsevier Ltd. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 158.92K | Year: 2012

DESCRIPTION (provided by applicant): This Phase I SBIR project seeks to develop specialized protein-polymer nanoparticles that are engineered to a therapeutic drug to counter the ill effects following exposure to organophosphate (OP) insecticides. The concept for these nanoparticles is based on 'customized, triggered-release' in which the membrane of a polymerized liposome nanoparticle (PLN) displays functional acetylcholinesterase, the primary target for OPs, while a therapeutic cargo is encapsulated (e.g., oxime). During an OP exposure, the AChE is inhibited (the same as exogenous ChE) to cause protein changes that later the polymeric nanoparticle membrane allowing the oxime cargo (various mechanisms possible) to be released and immediately available to restore exogenous ChE. Because the PLNs are customized and specific to OPs, PLN-AChE nanoparticles will not produce unwanted, high concentrations of the therapeutic agents in the body without OP exposure. In this application, we will develop and subsequentlyshow that AChE-PLNs can be generated with functional enzyme and are selectively inhibited by organophosphates (OP). We will further demonstrate that small molecule cargo can be loaded and stored in functional AChE-PLNs that reaction with OPs releases theentrapped cargo. We will produce 25 mg each of three functional, intact ChE-PLNs in readiness for the Phase II portion of this RandD project. PUBLIC HEALTH RELEVANCE: Citizens can be exposed to organophosphate (OP) insecticides via domestic application, aerial spraying, crops, as a pediculicide, and through the food chain. Accidental exposure to OP- containing pesticides can cause many tiers of toxicity, injury or be fatal to humans. For decades, only high-level exposures to OPs receive medical attention because low, chronic exposures have gone unchecked largely because they can asymptomatic, usually manifesting illnesses through accumulated exposures. If therapeutic measures could be available through a preventative process and highly specific toward OP exposures, a reduction in short- and long- term ill health effects could be expected.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 298.69K | Year: 2007

DESCRIPTION (provided by applicant) This SBIR project is in response to the call for the development of field-deployable or wearable personal sensors for monitoring point-of-contact exposures to airborne chemicals through biosample testing. The broad objective of this proposal is to develop an extremely sensitive and selective biosensor device capable of detecting and discriminating proteins in human serum samples taken from patients suspected of being exposed to potentially harmful levels of organophosphate-based pesticides. This represents a novel approach in biomarker analysis because each organophosphate (OP) pesticide results in a distinct protein "fingerprint" structure that can be identified, distinguished from other agents and their conjugates, and quantified. Using ATERIS Technologies novel sensor thin polymer film technology, reporter domains will be customized with specific protein-recognition molecules that detect the OP poisoned proteins. This will make it possible to develop an inexpensive, yet highly rapid, sensitive, and accurate device to analyze exposure to OP pesticides, assess the type and extent of OP agent exposure and then this information will guide the therapeutic intervention necessary. The major milestones in this Phase I SBIR project are first to isolate biorecognition proteins capable of discriminating between native and OP-poisoned human proteins, then show proof-of-principal for the sensitivity and reliability of the film sensor element. In the Phase II of this program, the detection films will be incorporated into a reader device and the reproducibility and accuracy of detection of OP-modified proteins in actual serum samples will be determined. The data generated will guide the design of the commercial biosensor device. The end user of such a device will be the field personnel likely to be exposed to OP pesticides and clinical laboratories likely to encounter patients that are suspected to have been exposed to OP chemical agents.

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