Kwon S.J.,The Interdisciplinary Center |
Mora-Pale M.,The Interdisciplinary Center |
Lee M.-Y.,Solidus Inc. |
Dordick J.S.,The Interdisciplinary Center |
Dordick J.S.,Rensselaer Polytechnic Institute
Current Opinion in Chemical Biology | Year: 2012
The enormous pool of chemical diversity found in nature serves as an excellent inventory for accessing biologically active compounds. This chemical inventory, primarily found in microorganisms and plants, is generated by a broad range of enzymatic pathways under precise genetic and protein-level control. In vitro pathway reconstruction can be used to characterize individual pathway enzymes, identify pathway intermediates, and gain an increased understanding of how pathways can be manipulated to generate natural product analogs. Moreover, through in vitro approaches, it is possible to achieve a diversification that is not restricted by toxicity, limited availability of intracellular precursors, or preconceived (by nature) regulatory controls. Additionally, combinatorial biosynthesis and high-throughput techniques can be used to generate both known natural products and analogs that would not likely be generated naturally. This current opinion review will focus on recent advances made in performing in vitro pathway-driven natural product diversification and opportunities for exploiting this approach for elucidating and entering this new chemical biology space. © 2012 Elsevier Ltd. Source
Lee M.-Y.,Solidus Inc. |
Dordick J.S.,Rensselaer Polytechnic Institute |
Clark D.S.,University of California at Berkeley
Methods in Molecular Biology | Year: 2010
Due to poor drug candidate safety profiles that are often identified late in the drug development process, the clinical progression of new chemical entities to pharmaceuticals remains hindered, thus resulting in the high cost of drug discovery. To accelerate the identification of safer drug candidates and improve the clinical progression of drug candidates to pharmaceuticals, it is important to develop high-throughput tools that can provide early-stage predictive toxicology data. In particular, in vitro cell-based systems that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process. The in vitro techniques that provide a high degree of human toxicity prediction will be perhaps more important in cosmetic and chemical industries in Europe, as animal toxicity testing is being phased out entirely in the immediate future. We have developed a metabolic enzyme microarray (the Metabolizing Enzyme Toxicology Assay Chip, or MetaChip) and a miniaturized three-dimensional (3D) cell-culture array (the Data Analysis Toxicology Assay Chip, or DataChip) for high-throughput toxicity screening of target compounds and their metabolic enzyme-generated products. The human or rat MetaChip contains an array of encapsulated metabolic enzymes that is designed to emulate the metabolic reactions in the human or rat liver. The human or rat DataChip contains an array of 3D human or rat cells encapsulated in alginate gels for cell-based toxicity screening. By combining the DataChip with the complementary MetaChip, in vitro toxicity results are obtained that correlate well with in vivo rat data. © 2010 Humana Press, a part of Springer Science+Business Media, LLC. Source
Samsung and Solidus Inc. | Date: 2012-05-17
There is provided a fluid discharging device including: a first pressure generating unit generating a first pressure for discharging a fluid; a second pressure generating unit generating a second pressure for discharging a fluid, and being controllable so as to change a magnitude of the second pressure; and a nozzle discharging the fluid pressurized by the first and second pressure generating units.
Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase II | Award Amount: 500.00K | Year: 2009
This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). This Small Business Technology Transfer (STTR) Phase II project will address further development and commercialization of a multi-enzyme lead optimization chip (Multizyme Chip) for high-throughput generation of lead compound analogs coupled with cell-based screening for the rapid identification of biologically active derivatives. Such a capability directly impacts a key bottleneck in drug discovery; namely, the efficient optimization of lead compounds to develop drugs with optimal pharmacological properties. Solidus Biosciences, Inc. proposes to combine six biocatalysis with pharmacological screening to provide rapid identification of biologically active compounds against cell-specific targets, which is a new paradigm for lead optimization. Moreover, the Multizyme Chip platform will be well-suited for lead optimization in related industries, including agrochemicals, cosmetics, and cosmeceuticals. The Solidus technology will thus improve the competitiveness and efficiency of the pharmaceutical, cosmetics, and chemical industries, and will serve as a rich source of new and improved commercial products. The broader impacts of this research are the advances that Solidus Biosciences will achieve toward generating better and safer drugs, reducing the cost to develop these drugs, and increasing the overall efficiency of the pharmaceutical industry. Solidus will generate Multizyme Chips for purchase by pharmaceutical and biotechnology companies to facilitate their lead optimization programs, particularly those involving natural product-derived and complex synthetic small molecule leads. Cryopreservation techniques developed in Phase II will enable the sale of chips and chip-handling devices produced during Phase I, and will allow seamless penetration of the Solidus technology platform into the company's target markets.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 200.61K | Year: 2008
DESCRIPTION (provided by applicant): Solidus Biosciences, Inc. in partnership with the University of California, Berkeley, and Rensselaer Polytechnic Institute are proposing to address a critical need in drug safety technology through its proprietary meta bolic stability chip (or Metabolizing Enzyme Stability Assay Chip, or MesaChip) for high-throughput analysis of drug candidate metabolism. The MesaChip is being developed to provide the pharmaceutical industry user with the ability to mimic the first-pass metabolism of the human liver. While in recent years there has been a dramatic increase in the number of new chemical entities (NCEs) and screenable drug targets, such increases in productivity have not translated into an increased number of new drug appr ovals, in part because of the high failure rate due to toxicity of the NCE or its metabolite(s). A critical component of drug safety evaluation is the metabolic stability of a drug candidate, which reflects the susceptibility of a drug candidate to be meta bolized and the rate of such metabolism. Early stage metabolic stability analysis, however, is currently limited by the inherent low throughput of methods available that provide accurate quantitative measurement of drug candidate metabolism. As a result, a ccurate information required for early-stage high-quality decision making is lacking. The specific aims of this Phase I project are to: 1. Develop well-based fluorescence assays that enable determination of P450-catalyzed substrate oxidation rates from con current measurements of oxygen and NADPH consumption and of H2O2 formation. 2. Verify using LC-MS that the above rate measurements can be used to calculate accurate rates of P450-catalyzed oxidation reactions. 3. Adapt the well-plate assay techniques devel oped in Aim 1 to a high-throughput microarray format (MesaChip) based on the MetaChip platform that involves P450s incorporated into microspots (lt 30 nL) on a functionalized glass slide. Once fully developed, the MesaChip will provide a robust and high-th roughput technology platform capable of providing pharmaceutical researchers with the information needed to predict the in vivo metabolic stability of drug candidates, and thus help to decide which compounds are brought forward for lead optimization. This capability is also a critical precursor to the widespread adoption of personalized medicine, where differences among individuals in drug metabolism can be predicted, thereby providing information on the potential outcome of drug therapy at the individual p atient level. The goals of this STTR project, therefore, fit the goals of the National Institutes of Health. The drug discovery process is an investment-intensive, high-risk endeavor that results in low yields of effective and safe drugs; a problem that is confounded by the significant lack of information that exists in predicting the metabolic fate of drug candidates, in general, and in predicting the reactivity of drug candidates in the human body. The proposed STTR project for the development of Solidus Bioscience's MesaChip technology has significant relevance to public health by providing pharmaceutical researchers with the information needed to predict the in vivo metabolic stability of drug candidates, and thus help to decide which compounds are broug ht forward for lead optimization and the ultimate development of better and safer drugs.