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Compartmentalised screening by microfluidic control

a microfluidic control and filtering technology, applied in the field of filtering and filtering, can solve the problems of difficult identification of the structure of a hit compound, complicated synthesis and analysis, and less widely adopted, and achieve the effects of high-throughput filtering of compounds, low cost, and rapid screening

Inactive Publication Date: 2007-04-26
PRESIDENT & FELLOWS OF HARVARD COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022] We have now developed a methodology for screening of compounds, not encoded by genetic elements, using a compartmentalised microcapsule system based on that described in Griffiths & Tawfik (1998). The novel method according to the present invention uses systems and methods for the control of fluidic species to permit the rapid, high-throughput screening of compounds for activity against a target at low cost in a manner compatible with modem HTS approaches.

Problems solved by technology

This method is much less widely adopted due to a series of limitations including: the need for solid phase synthesis; difficulties characterizing the final products (due to the shear numbers and small scale); the small amounts of compound on a bead being only sufficient for one or a few assays; the difficulty in identifying the structure of a hit compound, which often relies on tagging or encoding methods and complicates both synthesis and analysis.
Combichem has so far, however, generated only a limited number of lead compounds.
However, there are to date few studies that directly compare the performance of VS and HTS, and further validation is required.
Despite all these developments, current screening throughput is still far from adequate.

Method used

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  • Compartmentalised screening by microfluidic control

Examples

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example 1

Microfluidic Device for Screening Using In Vitro Compartmentalisation

[0328] A schematic representation of the microfluidic device is shown in FIG. 18. Microchannels are fabricated with rectangular cross-sections using rapid prototyping in poly(dimethylsiloxane) (PDMS) (McDonald and Whitesides, 2002) and rendered hydrophobic as (Song and Ismagilov, 2003). Syringe pumps were used to drive flows (Harvard Apparatus PHD 2000 Infusion pumps). For aqueous solutions, 250 μl Hamilton Gastight syringes (1700 series, TLL) with removeable needles of 27-gaugeare used with 30-gauge Teflon tubing (Weico Wire and Cable). For the carrier fluid, 1 ml Hamilton Gastight syringes (1700 series, TLL) are used with 30-gauge Teflon needles with one hub from Hamilton (Song and Ismagilov, 2003). The carrier fluid is 9% (v / v) C6F11C2H4OH in perfluorodecaline (PFD) (Song et al., 2003). The microfluidic device consists of a series of interconnected modules. Each module has a specific function. These include mod...

example 2

Screening for Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors Using Microcapsules in Microfluidic Systems

[0340] PTP1B is a negative regulator of insulin and leptin signal transduction. Resistance to insulin and leptin are hallmarks of type 2 diabetes mellitus and obesity and hence PTP1B is an attractive drug target for diabetes and obesity therapy (Johnson et al., 2002). Using a microfluidic device as described in Example 1, we describe how PTP1B inhibitors can be screened using microcapsules in a microfluidic system.

[0341] All water-soluble reagents are dissolved in (25 mM HEPES, pH 7.4, 125 mM NaCl, 1 mM EDTA), a buffer compatible with PTP1B activity. A solution of the target enzyme (human recombinant PTP1B, residues 1-322; Biomol Research Laboratories, Inc.) at 50 mU / ml and a solution of either a) 100 μM compound 2 (FIG. 17), which has a bis-difluoromethylene phosphonate and is a known PTP1B inhibitor (Johnson et al., 2002), or

[0342] b) 100 μM hydrocinnamic acid (Aldrich), ...

example 3

Screening of PTP1B Inhibitors from a Compound Library

[0344] 96 aqueous mixtures are made on ice (to prevent reaction). The first mixture contains 100 μM compound 2 (FIG. 17), which has a bis-difluoromethylene phosphonate and is a known PTP1B inhibitor (Johnson et al., 2002), and a pre-defined ratio of Qdot™ Streptavidin Conjugates with emmission maxima at 585 nm, 655 nm and 705 nm (Quantum Dot Corporation, Hayward Calif.) in a buffer compatible with PTP1B activity (25 mM HEPES, pH 7.4, 125 mM NaCl, 10% glycerol, 1 mM EDTA) (Doman et al., 2002). The 95 other aqueous mixtures are identical to the above but each contain one of 95 carboxylic acids from the Carboxylic Acid Organic Building Block Library (Aldrich) in place of compound 2, and different ratios of Qdot™ Streptavidin Conjugates with emission maxima at 585 nm, 655 nm and 705 nm. In all mixtures the concentration of the 705 nm Qdot™ Streptavidin Conjugates is 100 nM, and the concentrations of the 585 nm and 655 nm Qdot™ Strept...

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Abstract

The invention describes a method for the identification of compounds which bind to a target component of a biochemical system or modulate the activity of the target, comprising the steps of: a) compartmentalising the compounds into microcapsules together with the target, such that only a subset of the repertoire is represented in multiple copies in any one microcapsule; and b) identifying the compound which binds to or modulates the activity of the target; wherein at least one step is performed under microfluidic control. The invention enables the screening of large repertoires of molecules which can serve as leads for drug development.

Description

RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 120, to PCT Application No. GB2004 / 001362 filed Mar. 31, 2004, the entirety of which is incorporated herein by reference. [0002] The present invention relates to a method for selection of compounds from a library of compounds using systems and methods for the control of fluidic species and, in particular, to systems and methods for the electronic control of fluidic species. The method of the invention is particularly applicable to selection of low molecular weight compounds such as candidate drugs for potential activity against any desired drug target.BACKGROUND TO THE INVENTION [0003] The present invention relates to methods for use in the identification of molecules which bind to a target component of a biochemical system or modulate the activity of a target. [0004] Over the past decade, high-throughput screening (HTS) of compound libraries has become a cornerstone technology of pharmaceutical research....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C40B40/04B01F3/08B01F5/02B01F5/06B01F13/00B01L3/00C12Q1/68C40B50/08G01N15/14G01N33/53G01N33/543G01N33/555
CPCB01F3/0807C12Q2563/159B01F5/0646B01F5/0647B01F5/0655B01F13/0062B01F13/0071B01F13/0076B01J2219/00576B01J2219/00596B01J2219/00599B01J2219/00657B01J2219/00664B01J2219/00702B01L3/502761B01L3/502784B01L2200/0647B01L2200/0673B01L2300/0816B01L2300/0864B01L2300/0867B01L2400/0406B01L2400/0415B01L2400/0487C40B50/08G01N33/5432G01N2015/149G01N2500/10B01L2200/0652C12Q2565/119B01F5/0256G01N33/5008G01N33/5044B01J2219/00666B01F23/41B01F25/4331B01F25/4338B01F25/433B01F33/3011B01F33/3031B01F33/3021B01F25/23B01F23/4143B01F23/4145B01J19/0046C12Q1/42G01N15/14G01N21/6428G01N33/573G01N2021/6439G01N2333/916G01N2500/04
Inventor GRIFFITHS, ANDREWWEITZ, DAVIDLINK, DARRENAHN, KEUNHOBIBETTE, JEROME
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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