The advent of genomic sciences has led to a new concept of drug discovery. Genomics-derived drugs from the new concept consist of DNA-related drugs, protein drugs and small molecule drugs that react with a target gene or protein. Some of these therapeutic agents have been promoted to the human clinical stage. However, it is not easy to obtain efficacy through a conventional delivery technologics. A delivery system, aka “vector”, is necessary for efficient delivery of the DNA-related drugs such as genes, antisense compounds and ribozymes. In addition, new delivery systems are required for the practical use of therapeutic protein drugs. New delivery systems will be necessary for other genomics-derived compounds such as peptides. As indicated above, new delivery systems will certainly play an important role in the future development of the new drugs. This review will summarize the importance and contribution of DDS to genornics-based medicine.

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Today, technologies and methods for the rapid identification of functional genes are required with the development of genome informatics. The hammerhead ribozyme, one of the RNA enzymes, is useful for identification of genes by phenotypic changes of cells because of its ability to knock down intracellular expression of target genes by cleaving mRNA specifically. Since the ribozyme has the sequence that is complementary to that of mRNA as the ribozyme target, we can identify a target gene from sequence of a ribozyme by homology search with databases of DNA sequence. Moreover, we improved the efficiency of ribozymes by a combination of the cleavage activity of a ribozyme and the unwinding activity of an endogenous RNA helicase(s) as a hybrid ribozyme. By creating a library of the hybrid ribozyme with randomized substrate-binding arms that cleave multiple mRNAs as knock down library, we can correlate ribozymes and genes with a specific phenotype using the library. Therefore, the system with the ribozyme library should be a powerful tool for identification of functional genes in the post-genome era.

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This document is a review of the course of genomic drug discovery and its clinical applications. Several key steps in the course of genomic drug discovery are followed as genomic research, gene discovery including susceptibility genes for diseases and drug response genes, functional and structural genomics, new specific drug target validation, rational drug design, lead hit & optimization, preclinical studies and efficient clinical studies with polymorphism analysis and SNPs generation. The most critical points and successful promises of drug discovery lie in the potential to understand disease processes at the molecular level, to determine the optimal molecular targets for drug design, and to select the lead compounds that modulate a protein's activity and have optimal absorption, distribution, metabolism, excretion and toxicity properties, using bioinformatics and structural genomics. Genomic research in the human genome project will lead not only to identification of more relevant drug targets leading to more specific drug therapies, but also to DNA-based diagnosis, leading to earlier treatment or change in lifestyles and tailor-made treatments specific to disease-subtype, including treatments which avoid side-effects. Furthermome, this is focused on the successful new drug discovery on molecular target therapy of cancers, e. g. (1) imatinib (Glivec^®) for chronic myelogenous leukemia and acute lymphocytic leukemia with Ph¹ chromosome, (2) trastuzumab (Herceptin^®) for breast cancer with HER2 overexpression, (3) rituximab(Rituxan^®) for malignant B-cell lymphoma and the (4) ZD 1839 (Iressa^®) for non-small cell lung cancer.

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The initial results of DNA sequencing of the human genome were published in February 2001. Life sciences are now giving priority to the explication of the functions of genes and proteins over research into DNA sequencing. Life sciences are making great strides with the release of genomic information, and the results obtained will be utilized in drug research. Thus, drug discovery in the 21st century will be forced to shift to genomic approach. The information may be utilized in all the steps of conventional drug research. Above all, it is expected to be most useful in the identification of targets, the first step in drug research, as well as in clinical trials, the last step. Examples are emerging that elucidation of orphan receptors/ligands and transcriptome analyses are useful in identifying drug target molecules. To date, the science of drug discovery has made good use of the accomplishments of all the life sciences. In the future, genomic drug discovery is expected to open out an innovative drug research by merging conventional methods of drug discovery with such multidisciplinary technologies as bioinfomatics, structural biology, and computer and systems technology, based on genomic information. It is hoped that this will produce drugs of higher quality. Such advances are expected to improve the QOL and have a medicoeconomic effect.

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In recent years, a variety of recombinant bioactive proteins, such as cytokines, have been produced for drug therapies. However, since these recombinant proteins are quite unstable in vivo, their clinical use as therapeutic agents requires frequent administration at a high dosage. This regimen disrupts homeostasis, resulting in severe adverse effects. To overcome these problems, bioactive proteins have been conjugated with water-soluble polymers such as polyethylene glycol (PEG). PEGylation can increase plasma half-lives, stability, and therapeutic potency, but application of PEGylation is limited, because PEGylation of proteins is mostly non-specific and targeted at all their lysine residues, some of which may be in or near the active-site. The resultant PEGylated proteins are heterogeneous and show marked lower bioactivity. To overcome these problems, site-specific PEGylation can be achieved via a free thiol that has been engineered into the proteins. But this approach was not successful because there were extremely low yield of PEGylated proteins and a significant loss in activity due to introduction of a free thiol residue. We attempted to develop a new strategy for site-specific PEGylation (specific and effective attachment of PEG to the amino group at the N-terminus) to overcome these drawbacks mentioned above. In this review, we show the advantages of this site-specific PEGylation used TNFα as a model protein.

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