Chemical amplification for the synthesis of patterned arrays

Abstract

Radiation-activated catalysts (RACs), autocatalytic reactions, and protective groups are employed to achieve a. highly sensitive, high resolution, radiation directed combinatorial synthesis of pattern arrays of diverse polymers. When irradiated, RACs produce catalysts that can react with enhancers, such as those involved in autocatalytic reactions. The autocatalytic reactions produce at least one product that removes protecting groups from synthesis intermediates. This invention has a wide variety of applications and is particularly useful for the solid phase combinatorial synthesis of polymers.

Description

STATEMENT OF RELATED APPLICATIONS[0001] This application claims priority to U.S. Provisional Application Ser. No. 60 / 030,826 filed Nov. 14, 1996, hereby incorporated by reference in its entirety.[0002] Embodiments of the present invention relate to spatially defined chemical synthesis involving lithographic processes. In particular, embodiments of the present invention are directed to novel methods and compositions for synthesizing arrays of diverse polymer sequences, such as polypeptides and polynucleotides. According to a specific aspect of the invention, a method of synthesizing diverse polymer sequences, such as peptides or polynucleotides, is provided. The diverse polymer sequences are useful for example, in nucleic acid analysis, gene expression monitoring, receptor and nucleic acid binding studies, surface based DNA computation, and integrated electronic circuits and other miniature device fabrication.[0003] Methods of synthesizing polymer sequences such as nucleotide and pep...

AI Technical Summary

Benefits of technology

0014] Using the techniques disclosed herein, it is possible to advantageously irradiate relatively small. and precisely known locations on the surface of the substrate. The radiation does not directly cause the removal of the protective groups, such as through a photochemical reaction upon absorption of the radiation by the synthesis intermediate or linker molecule itself, but rather the radiation acts as a signal to initiate a chemical catalytic reaction which removes the protective group in an amplified manner. Therefore, the radiation intensity as used in the practice of the present invention to initiate the catalytic removal by a catalyst system of protecting groups can be much lower than, for example, direct photo removal, which can result in better resolution when compared to many non-amplified techniques.

0015] The present invention is advantageous because it makes possible the synthesis of polymers of any desired chemical sequence at known locations on a substrate with high synthesis fidelity, small synthesis feature, and improved manufacturability. Embodiments of the present invention are useful in fabricating high density nucleic acid probe arrays or immobilizing nucleic acid sequences on a surface of a substrate. High density nucleic acid probe arrays provide an efficient means to analyze nucleic acids, to monitor gene expression and to perform computation.

0016] It is therefore an object of the present invention to provide methods of manufactuing high density polymer arrays using chemical amplification techniques. It is a further object of the present invention to provide methods of manufacturing polymer arrays using less time and lower radiation intensities to improve polymer purity, to improve the spatial resolution and contrast between polymer and substrate and to decrease the area on the substrate where polymer sequences can be synthesized allowing many and different polymer sequences on the same substrate. It is a still further object of the present invention to provide methods of removing protecting groups from synthesis intermediates in the formation of polymer sequences using photosensitive compounds to initiate catalytic reactions. It is an even still further object of the present invention to improve precision, contrast, and ease of manufacture in the production of polymer arrays.

Problems solved by technology

For example, the technique discussed in Geysen et al. is limited to producing 96 different polymers on pins spaced in the dimensions of a standard microliter plate.

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