Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Utility Patent
1998-12-18
2001-01-02
Venkat, Jyothsan (Department: 1618)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S006120, C435S007100, C436S174000, C422S130000, C422S131000, C422S132000, C422S134000, C422S187000, C422S186220, C422S198000, C422S198000
Utility Patent
active
06168914
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of chemical synthesis, and in particular to the synthesis of various chemicals onto supports in a parallel manner to produce a combinatorial collection of compounds.
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BACKGROUND OF THE INVENTION
Large collections (libraries) of organic molecules have emerged as important tools for the successful identification of useful compounds. Such libraries have typically been synthesized using combinatorial approaches (see, e.g., Gallop et al., 1994; Gordon, E. M. et al., 1994). Several different methods have been used to assemble combinatorial libraries of various compounds. One such methodology was disclosed in Geysen, et al. Geysen's method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. A second method of peptide or oligonucleotide synthesis was developed by Affymax Technologies N.V. and disclosed in U.S. Pat. No. 5,143,854. The Affymax method involves sequentially using light for illuminating a plurality of polymer sequences on a substrate and delivering reaction fluids to said substrate. This method of synthesis produces large numbers, but relatively small quantities of products. A further method and device for producing peptides or oligonucleotides is disclosed in Houghton, E.P.O. 196174. Houghton's apparatus is a polypropylene mesh container or sac, similar to a tea-bag, which encloses reactive particles.
While combinatorial chemistry synthetic schemes such as the methods described above can generate large numbers of different compounds with a minimum number of steps, they have certain disadvantages. As mentioned above, some of the methods are capable of producing only limited quantities of each compound. Furthermore, the compounds are typically synthesized and screened in “pools” or “batches.” This can result in loss of potentially valuable information during screening if, for example, a particular pool contains compounds which possess both agonist and antagonist activities. Further, once a pool is identified as containing a potentially active compound, the identity of the active compound must be determined, This identification or decoding requires some type of deconvolution or tagging protocol, requiring additional steps to identify the active compound.
Parallel synthesis strategies do not suffer from the above-mentioned disadvantages of combinatorial approaches, as a single compound is generated and assayed (see, e.g., Sugarman et al., U.S. Pat. No. 5,503,805, issued Apr. 2, 1996). The disadvantage of parallel synthesis strategies is that presently-available instrumentation for carrying out such syntheses is costly and complex, requiring a large number of valves, separate pieces of tubing, and the like. Accordingly, it is generally not suitable for the synthesis of large numbers (e.g., >100) of compounds. Currently available parallel synthesis instruments are typically limited in their capacity to between 12 and 24 reaction vessels for automated instruments and 96 reaction vessels for manual instruments.
Thus, there is a need for a simple and efficient systems and methods for synthesizing large numbers of compounds, that do not suffer from the above disadvantages of combinatorial approaches or the complexity and limitations of currently-available parallel synthetic approaches. The present invention provides such a method.
SUMMARY OF THE INVENTION
The invention provides, in one aspect, a system for synthesizing chemicals onto membrane supports in a parallel manner. The system includes a plurality of middle plates and a pair of end plates. Each middle plate has a plurality of holes arranged in a two dimensional array, e.g., square or rectangular array, having x and y axes. The middle plates are stackable on each other and adapted to receive interleaving sheets of membrane to form a three dimensional array of reaction zones having x, y and z axes and defining Z (x,y) reaction planes. Alternatively, the holes in the middles plates may be defined by wells or reaction vessels for holding solid supports, such as beads. In such a three dimensional array, reaction zones having common (x,y) coordinates and different z coordinates form a “column” of reaction zones.
The middle plates may be formed of any material that is resistant to the reagents, building blocks and/or solvents which will be circulated through the device. Preferably, the middle plates are constructed on a non-compliant material, such as stainless steel, with one particular embodiment employing 0.005 inch thick 316 stainless steel. Alternatively, the middle plates may be formed of a material that is somewhat compliant, so that when the middle plates are clamped together about a membrane, a fluid-tight seal is achieved between adjacent reaction zones in the same (x,y) plane. Other exemplary materials suitable for use as middle plates with the present invention include polytetrafluoroethylene (PTFE) or “KALREZ” sheets. The sheets typically have a thickness of between about 0.002″ and 0.2″; preferably between about 0.003″ and 0.05″, and more preferably from about 0.005″ and 0.01″.
The membranes may be interleaved such that each sheet of membrane is flanked by a set or pair of middle plates, such that a stack of middle plates and membranes would contain, in sequence, a middle plate, membrane, middle plate, middle plate, membrane, middle plate, middle plate, membrane, etc. Further, several sheets of membranes may be interposed in between a single pair of middle plates, thus increasing the surface area available for chemical synthesis of a compound at each reaction zone. The membranes may be formed of, e.g., polypropylene, polyethylene, polytetrafluoroethylene (PTFE) polyacrylate terpolymer, PTFE polyacrylamide terpolymer, or fluoropolymer membrane grafted with styrene, acrylate, or acrylamide. Alternatively, the middle plates may be used to define wells or reaction vessels for holding other types of solids supports, such as beads.
A pair of end plates is also provided, and the middle plates are positioned between the end plates. The end plates include fluid guides,
Antonenko Valery V.
Campbell David A.
Gavin Robert M.
Ida Satoru
Muir Arthur H.
Gibby Darin J.
Glaxo Wellcome Inc.
Ricigliano Joseph W.
Stevens Lauren L.
Venkat Jyothsan
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