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Isolating biological modulators from biodiverse gene fragment librariesRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidIsolating biological modulators from biodiverse gene fragment libraries description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050287580, Isolating biological modulators from biodiverse gene fragment libraries. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to the field of screening gene libraries, and more particularly to the generation and screening of natural domain libraries derived from organisms with known genomic sequences. Methods for increasing the diversity of such biodiverse gene fragment libraries further by mutagenesis procedures are described. The present invention also provides the means by which a wide range of peptide-based therapeutics, prophylactics and diagnostic reagents may be developed. [0002] General [0003] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variation and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in the specification, individually or collectively, and any and all combinations or any two or more of the steps or features. [0004] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein. [0005] Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. All references cited, including patents or patent applications are hereby incorporated by reference. No admission is made that any of the references constitute prior art. [0006] As used herein the term "derived from" shall be taken to indicate that a specific integer may be obtained from a particular source albeit not necessarily directly from that source. [0007] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. BACKGROUND TO THE INVENTION [0008] Biological interaction/activities, such as protein:protein interactions, antigen: antibody interactions, protein:nucleic interactions, protein: ligand interactions and nucleic acid:nucleic acid interactions are involved in a wide variety of processes occurring in living cells. For example, agonism and antagonism of receptors by specific ligands, antibody-antigen interactions, including drugs, hormones, second messenger molecules, etc. may effect a variety of biological processes such as gene expression, cellular differentiation and growth, enzyme activity, metabolite flow and metabolite partitioning between cellular compartments, amongst others. DNA:protein and RNA protein interactions are well known for their effects in regulating gene expression in both prokaryotic and eukaryotic cells, in addition to being critical for DNA replication and in the case of certain viruses, RNA replication. In cases where the propagation of cells is deleterious such as the replication of a pathogen or of a cancer cell, agents which target biological interaction/activities or functional structures, are suitable candidates for therapy. For example, agents that block the function of membrane channels or disrupt cytoplasmic membranes by other means, are attractive targets for anti-microbial therapies against pathogens. Further, agents that interact with antigen-specific or non-specific functions of the immune system may provide immunological modulators or vaccines for allergy, autoimmunity, infectious disease, fertility and invenomation. For example, agents that have the antigenicity of microbial antigens, tumour antigens, allergens or autoantigens may be used for vaccines or immunotherapy. [0009] Undesirable or inappropriate gene expression and/or cellular differentiation, cellular growth and metabolism may also be attributable, at least in many cases, to biological interaction/activities involving the binding and/or activity of proteinaceous molecules, such as transcription factors, peptide hormones, receptor molecules and enzymes, amongst others. In these cases, therapies can be envisaged which block such inappropriate interactions and/or which block the formation of inappropriate cellular structures. [0010] Production of Peptides by Recombinant DNA Techniques [0011] Peptides that can mediate or interfere with a diverse range of biological functions include natural peptides and peptides synthesised to represent a portion or a modified portion of a molecule known to mediate a target function. One source of such peptides are random peptide libraries constructed with random (or semi-random) oligonucleotides ligated into cloning sites of a plasmid or phage vectors. [0012] Vectors containing DNA encoding different peptides are transfected or transformed into bacteria or other hosts and cloned by standard plaque or colony purification procedures. Clones producing peptides with a desired activity can be isolated by a variety of screening or selection procedures which are fundamentally the same as the screening procedures used to detect polypeptides encoded by cDNA or cDNA fragments. These include the production of peptides as fusions with the coat proteins of bacteriophage or fusions with bacterial surface proteins so the peptides can be used as tags for affinity purification procedures; the production of peptides from hosts infected with phage or transformed with plasmids to produce arrays of colonies or plaques which can be screened for ligand-binding activity or biological activity such as inhibiting the growth target bacteria or inducing the activation of genes in target bacteria; and in positive selection strategies such as the two hybrid cloning systems, where the peptide produced in the host microorganism binds to target proteins to form complexes which activate the expression of the reporter genes cloned into the same host. One of the significant advantages of phage display technology is that it enables the construction of libraries with very large complexities--ie. 10.sup.10 to 10.sup.11 individual clones. [0013] Likewise, in `reverse two hybrid` or `split two hybrid` systems, libraries of appropriately expressed peptides can be screened for blockers of particular protein/protein interactions, which in turn reduces the expression of counter selectable reporter genes encoding toxic products. [0014] Modification of Peptides for Utility and Optimisation [0015] Once the active peptide or a ligand binding peptide has been identified they can be modified by a variety of procedures to optimise their utility. Modification may include: alterations in the amino acid residues which engage the target to improve their binding specificity and affinity; modifications which affect the display of the peptide including the valency of binding and constraint of particular conformations; and modifications to attach further functional moieties such as markers, toxins and co-activators. [0016] Synthetic peptides can include residues other than the 20 amino acids found in nature and/or can be cyclised by means such as oxidation of flanking cystein residues. In the case of peptides mimicking antibody epitopes, carriers containing the T-cell epitopes required to induce high affinity immune responses can be added by genetic techniques. [0017] Examples of Peptides that Modulate Biological Systems [0018] Peptides can be applied as therapeutics or lead molecules for designing therapeutics for disease including infection, cancer and metabolic disorders as well as agents for vaccines and immunotherapy, transplantation and diagnostics. The potential usefulness of such peptides has been demonstrated by the following examples [0019] Peptide Antimicrobial Agents [0020] The antimicrobial effect demonstrated by natural peptides produced by frogs and insects and artificially synthesised cationic peptides. A large variety of antibiotics are peptides or polypeptides. The granules of mammalian neutrophils produce families of antimicrobial polypeptides including azurocidin, cathepsin G and Cationic Antimicrobial Peptides (CAP57 and CAP37). In addition, neutrophils produce at least two families of antimicrobial peptides, the defensins and the bactenecins. Moreover, many natural antibiotics and antifungal drugs are composed of peptides. For example, the magainin family of antimicrobial .alpha.-helical peptides isolated from the skin of the African clawed toad, Xenopus Laevis form lethal pores in the cell membranes of certain microorganisms. Similarly, certain a-helical peptides derived from a variety of insect genera have antimicrobial activity, Recently, several rational design approaches have been used to isolate novel peptide antibiotics. For example, Tiozzo et al., used a "sequence template" approach in which candidate peptide sequences were designed from alignments of natural antimicrobial peptides [1]. The identification of virulence determinants in several pathogens presents other attractive targets for antimicrobial therapy. For example, Balaban and colleagues (2) have recently identified an autoinducer of virulence in Staphylococcus aureus that controls the production of bacterial toxins involved in pathogenesis. The toxin genes are induced by a regulatory RNA molecule, RNAIII that is induced by a threshold concentration of an endogenous protein RNAIII Activating Protein (RAP) [2]. Peptide inhibitors of RAP might be expected to act as virulence determinants. Indeed, a natural peptide inhibitor of RAP called RIP (RNAIII inhibiting peptide) is produced by a non-pathogenic strain of Staphylococcus aureus and appears to inhibit the RNAIII gene and to cause reduced virulence [2]. [0021] Peptide Modulators of Growth Regulation [0022] The ability of peptides to affect key modulators of growth regulation has been demonstrated by Brent and colleagues who used two hybrid screening to identified constrained peptide `aptamers` from combinatorial libraries which bind tightly to and inhibit the function of cyclin dependent kinase 2. This demonstrates the potential for treatment of neoplasms (3). Continue reading about Isolating biological modulators from biodiverse gene fragment libraries... Full patent description for Isolating biological modulators from biodiverse gene fragment libraries Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Isolating biological modulators from biodiverse gene fragment libraries patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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