Abstract: Methods and derivatized supports which are useful in solid-phase synthesis of peptides, oligonucleotides or other small organic molecules as well as arrays of ligands. The methods provide means to control the functional site density on a solid support. Some of the derivatized supports are polymer-coated or glycan-coated. Other methods for regenerating the surface of a used ligand array are also provided.

Abstract: Compositions and methods are provided for enhanced transdermal electrotransport of 17-hydroxy sterol compounds, including testosterone. The parent sterols are modified at the 17-hydroxy position by covalent attachment of a charged chemical modifier. The chemical modifier provides the parent sterol with enhanced transport properties and is hydrolyzed under physiological conditions to release the active parent compound.The composition comprises a 17-hydroxy sterol/chemical modifier complex, more generally represented by the formula (sterol--O--)C(O)--R--N(R.sup.1)(R.sup.2)(R.sup.3).sup.+. The portion of the complex derived from the chemical modifier is indicated by "C(O)--R--N(R.sup.1)(R.sup.2)(R.sup.3).sup.+ ", where N(R.sup.1)(R.sup.2)(R.sup.3).sup.+ represents a quaternary ammonium group and R.sup.1, R.sup.2, and R.sup.3 are independently selected from the group consisting of lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroalkyl, and heteroarylalkyl; or R.sup.1 and R.sup.

Abstract: The present invention relates to methods of delivering pharmaceutical agents across membranes, including the skin layer or mucosal membranes of a patient. A pharmaceutical agent is covalently bonded to a chemical modifier, via a physiologically cleavable bond, such that the membrane transport and delivery of the agent is enhanced.

Abstract: Peptides that bind to the interleukin-1 type I receptor (IL-1RtI) can be used to assay the amount of IL-1R, or an IL-1R agonist or antagonist, in a sample and comprise a sequence of amino acids selected from the group consisting of (1) WXXXGZ.sub.1 W (SEQ ID NO: 1) where Z.sub.1 is L, I, A, or Q; (2) XXQZ.sub.5 YZ.sub.6 XX (SEQ ID NO: 6) where Z.sub.5 is P or Aze where Aze is azetidine; and Z.sub.6 is S, A, V, or L; and (3) Z.sub.23 NZ.sub.24 SZ.sub.25 Z.sub.26 Z.sub.27 Z.sub.28 Z.sub.29 Z.sub.30 L (SEQ ID NO: 17) where Z.sub.23 is D or Y; Z.sub.24 is D or S; Z.sub.25 is S or W; Z.sub.26 is S or Y; Z.sub.27 is D or V; Z.sub.28 is S or W; Z.sub.29 is F or L; and Z.sub.30 is D or L; and where each amino acid is indicated by standard one letter abbreviation; and each X can be selected from any one of the 20 genetically coded L-amino acids or the stereoisomeric D-amino acids.

Abstract: A method for DNA reassembly after random fragmentation, and its application to mutagenesis of nucleic acid sequences by in vitro recombination is described. In particular, a method for the production of nucleic acid fragments or polynucleotides encoding mutant proteins is described. The present invention also relates to a method of repeated cycles of mutagenesis, shuffling and selection which allow for the directed molecular evolution in vitro of proteins.

Abstract: Nucleotide sequences encoding proteins of interest are isolated from DNA libraries using bacteriophage to link the protein to the sequence which encodes it. DNA libraries are prepared from cells encoding the protein of interest and inserted into or adjacent to a coat protein of a bacteriophage vector, or into a sequence encoding a protein which may be linked by means of a ligand to a phage coat protein. By employing affinity purification techniques the phage particles containing sequences encoding the desired protein may be selected and the desired nucleotide sequences obtained therefrom. Thus, for example, novel proteins such as monoclonal antibodies may be produced and conventional hybridoma technology avoided.

Abstract: An improved set of computer tools for forming arrays. According to one aspect of the invention, a computer system (100) is used to select probes and design the layout of an array of DNA or other polymers with certain beneficial characteristics. According to another aspect of the invention, a computer system uses chip design files (104) to design and/or generate lithographic masks (110).

Abstract: Means for simultaneous parallel sequence analysis of a large number of biological polymer macromolecules. Apparatus and methods may use fluorescent labels in repetitive chemistry to determine terminal monomers on solid phase immobilized polymers. Reagents which specifically recognize terminal monomers are used to label polymers at defined positions on a solid substrate.

Abstract: Methods for concurrently processing multiple biological chip assays by providing a biological chip plate comprising a plurality of test wells, each test well having a biological chip having a molecular probe array; introducing samples into the test wells; subjecting the biological chip plate to manipulation by a fluid handling device that automatically performs steps to carry out reactions between target molecules in the samples and probes; and subjecting the biological chip plate to a biological chip plate reader that interrogates the probe arrays to detect any reactions between target molecules and probes.

Abstract: A method and library for determining the sequence of monomers in a polymer which is complementary to a receptor. The method provides for formation of pooled (6) and separate (10, 12) products. Separate products are subjected only to subsequent pooled coupling steps. Each pooled product is subsequently divided for formation of pooled and separate products. The resulting polymer library includes groups of polymer products. A first group of products (42) is used to identify the monomer at a first location in a polymer that is complementary to a receptor. A second group of products (44) is used to identify the monomer at a second location in a polymer that is complementary to a receptor.

Abstract: A synthetic strategy for the creation of large scale chemical diversity is claimed. Solid-phase chemistry, photolabile protecting groups, and photolithography are used to achieve light-directed spatially-addressable parallel chemical synthesis of an array of polymers that are based on a target polymer. The array includes systematically substituted versions of the target polymer.

Abstract: Disclosed are methods for synthesizing very large collections of diverse pyrrolidine compounds on solid supports and synthetic compound libraries comprising pyrrolidine groups prepared by such methods.

Abstract: A method for synthesizing and screening oligonucleotides on a solid substrate. The method provides for the irradiation of a first predefined region of a substrate comprising immobilized nucleotides on its surface, without irradiation of a second predefined region of the substrate. The irradiation step removes a protecting group from the immobilized nucleotides. The substrate is contacted with a first nucleotide to couple the nucleotide to the immobilized nucleotides in the first predefined region without coupling in the second predefined region. At least a part of the first predefined region and at least a part of the second predefined region are subjected to further irradiation. The substrate is contacted with a second nucleotide, which couples to the immobilized nucleotides in at least part of the first and at least part of the second predefined regions. By repeating these steps, an array of diverse oligonucleotides is formed on the substrate.

Abstract: A device and method for efficiently synthesizing diverse molecular products on substrates. A parent vessel 200 contains a suspension of substrates. The suspension is pressurized with argon and transferred to a plurality of reaction vessels 201-209 in one or more reaction vessel banks where monomer addition reactions take place. Optionally, the substrates may be tagged with a tag monomer. A vortexing motor 300 vortexes the contents of reaction vessels 201-209 during monomer addition reactions to enhance synthesis. After the desired monomer and/or tag monomer addition reaction, the suspension is pressurized with argon and transferred back to parent vessel 200 for mixing. Thereafter, the suspension may be pressurized with argon and reallocated among reaction vessels 201-209 for further synthesis.

Abstract: A random peptide library constructed by transforming host cells with a collection of recombinant vectors that encode a fusion protein comprised of a DNA binding protein and a random peptide and also contain a binding site for the DNA binding protein can be used to screen for novel ligands. The screening method results in the formation of a complex comprising the fusion protein bound to a receptor through the random peptide ligand and to the recombinant DNA vector through the DNA binding protein.

Abstract: A synthetic strategy for the creation of large scale chemical diversity. Solid-phase chemistry, photolabile protecting groups, and photolithography are used to achieve light-directed spatially-addressable parallel chemical synthesis. Binary masking techniques are utilized in one embodiment. A reactor system, photoremovable protective groups, and improved data collection and handling techniques are also disclosed. A technique for screening linker molecules is also provided.

Abstract: Methods and compositions are described for immobilizing anti-ligands, such as antibodies or antigens, hormones or hormone receptors, oligonucleotides, and polysaccharides on surfaces of solid substrates for various uses. The methods provide surfaces covered with caged binding members which comprise protecting groups capable of being removed upon application of a suitable energy source. Spatially addressed irradiation of predefined regions on the surface permits immobilization of anti-ligands at the activated regions on the surface. Cycles of irradiation on different regions of the surface and immobilization of different anti-ligands allows formation of an immobilized matrix of anti-ligands at defined sites on the surface. The immobilized matrix of anti-ligands permits simultaneous screenings of a liquid sample for ligands having high affinities for certain anti-ligands of the matrix. A preferred embodiment of the invention involves attaching photoactivatable biotin derivatives to a surface.

Abstract: Methods and compositions are described for immobilizing anti-ligands, such as antibodies or antigens, hormones or hormone receptors, oligonucleotides, and polysaccharides on surfaces of solid substrates for various uses. The methods provide surfaces covered with caged binding members which comprise protecting groups capable of being removed upon application of a suitable energy source. Spatially addressed irradiation of predefined regions on the surface permits immobilization of anti-ligands at the activated regions on the surface. Cycles of irradiation on different regions of the surface and immobilization of different anti-ligands allows formation of an immobilized matrix of anti-ligands at defined sites on the surface. The immobilized matrix of anti-ligands permits simultaneous screenings of a liquid sample for ligands having high affinities for certain anti-ligands of the matrix. A preferred embodiment of the invention involves attaching photoactivatable biotin derivatives to a surface.

Abstract: A method and apparatus for preparation of a substrate containing a plurality of sequences. Photoremovable groups are attached to a surface of a substrate. Selected regions of the substrate are exposed to light so as to activate the selected areas. A monomer, also containing a photoremovable group, is provided to the substrate to bind at the selected areas. The process is repeated using a variety of monomers such as amino acids until sequences of a desired length are obtained. Detection methods and apparatus are also disclosed.

Abstract: Peptides which bind to selected receptors are identified by screening libraries which encode a random or controlled collection of amino acids. Peptides encoded by the libraries are expressed as fusion proteins of bacteriophage coat proteins, and bacteriophage are then screened against the receptors of interest. Peptides having a wide variety of uses, such as therapeutic or diagnostic reagents, may thus be identified without any prior information on the structure of the expected ligand or receptor.