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Advanced drug development and manufacturing

a technology for drug development and manufacturing, applied in the direction of material analysis using wave/particle radiation, instruments, x/gamma/cosmic radiation measurement, etc., can solve the problem of not being able to predict which chemicals will bind effectively to proteins, the same binding affinity, and the inability to validate the chemical

Inactive Publication Date: 2008-09-11
RGT UNIV OF CALIFORNIA
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0027]There remains a need for simpler methods for measuring binding affinities and selectiv

Problems solved by technology

The desire to hasten the identification of potentially important drugs, catalysts, chemical and biological sensors, medical diagnostics, and other materials is a constant challenge that has prompted the use of combinatorial synthetic and screening strategies for synthesizing these materials and screening them for desirable properties.
Since it is well known that even small changes to the structure of a molecule could affect its function, this assumption that a tagged chemical, i.e. a “surrogate”, has the same binding affinity as the untagged chemical may not be a valid one.
For these reasons, it is extremely difficult to predict which chemicals will bind effectively to proteins.
TABLE 1 shows that most of the listed screening methods have the same drawback: they require either radiolabeled chemicals, chemicals that have been altered with a fluorescent tag, or chemicals that have been altered with a metal tag.

Method used

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  • Advanced drug development and manufacturing
  • Advanced drug development and manufacturing
  • Advanced drug development and manufacturing

Examples

Experimental program
Comparison scheme
Effect test

first example

[0073]We measured the interaction between biotin and avidin to demonstrate that RPM could quantify the sulfur-containing small molecule (biotin, C10H16N2O3S) over the sulfur content of a protein (tetrameric avidin, Sigma-Aldrich, 16 sulfur atoms, see Korpela J. Avidin, a high affinity biotin-binding protein, as a tool and subject of biological research. Medical Biol. 1984, 62:5-26). Previous studies have shown that the ratio of sulfur in avidin-biotin:avidin is 19.5:16, or 1.22, see Green N M. Purification of Avidin. Meth Enzymol. 1970, XVIII(A):414-417. We incubated 500 micrograms of avidin in 1.0 ml of 0.20 millimolar biotin at pH 8.0 for 5 minutes and then centrifuged the sample for 3 hours at 7000 g using a Centricon YM-3 resulting in a concentrated avidin-biotin sample of 25-50 μl. We diluted the sample to 0.75 ml in TRIS buffer (pH 8.0), centrifuged for 2 hours at 7000 g, and repeated this process twice. We treated an avidin control sample identically. We used RPM to measure t...

second example

[0074]Our preliminary data show that RPM measures non-covalent protein-inhibitor complexes. We used di-zinc aminopeptidase (aAP) and its competitive inhibitor leucine phosphonic acid (LPA). LPA binds to aAP with a Ki of 6.6 μM at pH 8.0, see Stamper C et al. Inhibition of the aminopeptidase from Aeromonas proteolytica by L-leucinephosphonic acid. Spectroscopic and crystallographic characterization of the transition state of peptide hydrolysis. Biochemistry, 2001, 40:7035-7046. We incubated 500 micrograms of aAP in 1.0 mls of 0.20 millimolar LPA (>10×Ki) at pH 8.0 for 5 minutes. We centrifuged the aAP-LPA sample for 3 hours at 7000 g using a Centricon YM-3 resulting in a concentrated sample of 25-50 μl. We diluted this sample to 0.75 ml in TRIS buffer (pH 8.0), centrifuged for 2 hours at 7000 g, and repeated this process twice. We subjected two negative control samples to the same filtering conditions described above: The first control was 1.0 ml of 0.20 millimolar LPA, and the secon...

example 1

[0176]Binding of ziprasidone to protein receptors. A protein array may be prepared as described in G. MacBeath and S. L. Schreiber, “Printing Proteins As Microarrays For High-Throughput Function Determination,”Science, vol. 289, pp. 1760-1763, (2000). This protein array may be exposed to a solution of ziprasidone, which is the active ingredient in the drug Geodon™. Ziprasidone has a molecular formula of C21H20ClN4OS and the structure shown below.

[0177]The elements chlorine and sulfur may each be detected by x-ray fluorescence. After the array is exposed to the ziprasidone-containing solution, an EDAX Eagle Microprobe x-ray fluorescence microscope, for example, could be used to determine the receptor proteins that bind to the ziprasidone. The amount of ziprasidone that is associated with each receptor may be quantified by x-ray fluorescence.

[0178]None of the proteins of the array are expected to contain the element chlorine, so the chlorine x-ray fluorescence baseline may be assumed ...

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Abstract

X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 09 / 859,701, now U.S. Patent Application 20030027129 entitled “Method for Detecting Binding Events Using Micro-X-ray Fluorescence Spectrometry,” which was published on Feb. 6, 2003, and a continuation-in-part of U.S. patent application Ser. No. 10 / 206,524, now U.S. Patent Application 20040017884 entitled “Flow Method and Apparatus for Screening Chemicals Using Micro-X-Ray Fluorescence,” which was published on Jan. 29, 2004, and a continuation-in-part of U.S. patent application Ser. No. 10 / 621,825 filed Jul. 16, 2003, all hereby incorporated by reference herein. This application also claims the benefit of U.S. Provisional Application Ser. No. 60 / 850,594 filed Oct. 10, 2006, hereby incorporated by reference herein.STATEMENT REGARDING FEDERAL RIGHTS[0002]This invention was made with government support under Contract No. DE-AC52-06NA25396 awarded by the U.S. Department of Energy. The ...

Claims

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Application Information

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IPC IPC(8): G01N33/53G01N21/76G01N33/68G01N23/223
CPCG01N2500/04G01N33/566G01N23/2204G01N23/223G01N2223/076
Inventor BIRNBAUM, EVA R.KOPPISCH, ANDREW T.BALDWIN, SHARON M.WARNER, BENJAMIN P.MCCLESKEY, T. MARKSTEWART, JEFFREY JOSEPHBERGER, JENNIFER A.HARRIS, MICHAEL N.BURRELL, ANTHONY K.
Owner RGT UNIV OF CALIFORNIA
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