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The use of peptides in Diogenesis: a novel approach to drug discovery and phenomics.

The Diogenesis Process is an integrated drug discovery platform that allows target validation, partner identification, and the identification of small molecule drug candidates for protein:protein interactions. Diogenesis utilizes the well-established methods of peptide display, synthetic and recombinant peptide production, in vitro biochemical and cell-based testing to form a universal drug discovery engine with distinct advantages over competing protocols. The process creates a library of diverse peptides, and selects rare and unique binders that identify and simplify surface "hot spots" on protein targets through which target activity can be regulated. In many cases, these peptide "Surrogates" have the minimal sequence and structural information needed to induce a change in the biological activity of the target; in pharmacological terms, only after inducing agonism or antagonism. The use of Surrogates in hot spot identification also allows subdivision of rather large surface domains into smaller domains that alone, or in combination with another subdomain, offers sufficient territory for modification of target activity. These Surrogates, in turn, provide the necessary ligands to develop appropriate Site Directed Assays (SDAs) for each essential subdomain. The SDAs provide the screening mode for finding competitive small molecules by high throughput screening. The other arm of the Diogenesis system is an application in the new area of "Phenomics." This part of the discovery process is a form of phenotypic analysis of genomic information that has also been referred to as "functional" genomics. Phenomics, done via the Diogenesis system, uses peptide Surrogates as modifiers of the activity of, and identifiers of the partners of, gene products of known and unknown function. Actually, in many instances, the same Surrogate isolated for use in Phenomics will be used to create SDAs for discovery of small molecule drug candidates. In this simple fashion, the two applications of Diogenesis are integrated to provide savings in research time and money.