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I believe that the contents of this page have changed. I'm therefore going to cut and paste the entire page, so that future changes can be monitored........
The Diogenesis® Process
DGI BioTechnologies, Inc (DGI) has developed a proprietary drug discovery platform, the
Diogenesis® Process, enabling the identification of small organic compounds for use as
pharmaceuticals. Currently, the screening process for hundreds of thousands of compounds is a
slow and laborious process and has not worked in cases where the natural ligand for the target
is a large protein. Overall, present screening processes remain time consuming and the most
costly part of the drug development process. The Diogenesis® Process combines several,
well-established methods to streamline drug discovery. The goal of Diogenesis® is to isolate
Surrogate molecules which sub-divide complex regions on a drug discovery target into small,
pharmacologically active sites called Hotspots. The Surrogates are then used to generate Site
Directed Assays that allow the identification of small molecule leads through High Throughput
Screening protocols.
DGI's Diogenesis® Process ensures that lead compounds interacting with
the hotspot have the necessary attributes of effective pharmacophores for
drug discovery.
The Diogenesis® Process was developed by DGI's Founder, President and CEO, Arthur J.
Blume, Ph.D. Prior to founding DGI, Dr. Blume held various senior positions at Lederle
Laboratories and the Roche Institute of Molecular Biology. He has over 25 years of experience
in basic research and drug discovery.
The Diogenesis® Process in Classical Drug Discovery
DGI's Diogenesis® Process combines well-established methods including recombinant antibody
and peptide production, phage display, and in vitro biochemical assays into a single, universal
drug discovery platform with distinct advantages over competing protocols. The process creates
and uses diverse scFvs and peptide Surrogates to identify surface "hot spots" (i.e.,
pharmacologically important sites) on protein targets. Hotspot identification aids in the discovery
of the single or multiple sites required for agonist or antagonist action. This, in turn, enables DGI
to develop appropriate Site Directed Assays (SDAs) necessary for identification of small
molecules reactive at the hotspots. By so defining the minimal active sites on proteins as
complicated as extracellular receptors or intracellular regulatory proteins, DGI can design the
SDAs necessary for a successful High Throughput Screening (HTS) effort. After
modification, these Surrogates can be used in competitive micro-volume HTS. Positive hits are
referred to as SOMERs® (i.e., Small Organic MoleculE Replacements).
The Diogenesis® Process is applicable to all forms of HTS assays
including Fluorescence Resonance Energy Transfer (FRET) and
Fluorescence Polarization (FP).
In DGI's experience, more than half of the peptide Surrogates binding to a particular target are
to hot spots thereby assuring the Company's ability to rapidly develop pharmacologically
important SDAs for HTS. The Surrogates also provide data to support three-dimensional
computational drug modeling and directed drug synthesis. For example, NMR analysis of a
surrogate bound to a protein has allowed definition of protein/ligand contact points that could be
an important adjunct for rational drug design.
As support for the Diogenesis® process, DGI has developed very large phage display libraries
of semi-synthetic scFv and peptides, each consisting of greater than 1011 independent clones
with a potential library complexity of >1012 members. The source of the V genes for the
antibody library (GRABLIB®) is both human and mouse genomic DNA. Our two primary
peptide libraries (RAPIDLIB®) consist of randomized 20mer and 40mer amino acids. In most
cases, secondary and tertiary libraries have been constructed following successful primary
biopanning. These consist of peptides undergoing controlled mutagenesis at the DNA level in
both framework and consensus regions.
DGI has successfully identified peptide and scFv agonists and antagonists
for a number of biologically important molecules including Growth
Hormone Receptor (human and "animal"), Insulin Receptor (IR), IgA
receptor, TNF receptors RI and RII and the IL-6 receptor. The
Diogenesis® process has also been used to isolate peptides that inhibited
the interaction of the important cell cycle protein p53 with MDM2. DGI
has also successfully screened approximately 100,000 small molecules
using SDAs for growth hormone.
The Company has identified hits with affinities ranging from 1-5 µM. Several of these small
molecules are have undergone directed chemical modifications as a means of increasing binding
affinities as part of the Company's drug development paradigm. Chemical modifications include
the generation of "Di-SOMERs".
In summary, the Diogenesis® process:
1.Reduces the time for drug lead discovery and significantly lowers development
time and costs;
2.Identifies compounds early in the discovery process with the attributes of
successful drugs;
3.Can sub-divides hotspots into several biologically active sites;
4.Permits the systematic characterization of large numbers of compounds;
5.Is applicable to all types of targets;
6.Is applicable to all types of HTS screening protocols and methodologies
7.Is capable of identifying small molecules as replacements for proteins; and
8.Has both a biological and informatic screening basis.
The Diogenesis® Process as an Aid for Genomics and
Phenomics
Phenomics can be defined as the identification of a gene's function. With completion of the
Human Genome Project in sight, Phenomics will become the focal point of tomorrow's drug
discovery effort by allowing Pharmaceutical and Biotechnology companies to rapidly validate
genes as potential targets for drug discovery. At present, researchers use genomic knockouts
and antisense approaches to determine the biological function of a gene. Unfortunately, neither
foretell, with any degree of accuracy, the outcome of modest changes in the biological activity of
a gene's protein product. As diseases are related to subtle changes in protein activity rather than
to complete loss or gain in any one protein, a method is needed to produce varying changes
in protein activity to determine a gene's relation to the specific disease process.
DGI's Surrogates offer the tools needed to modify protein activity and
validate the use of a gene as a target for drug discovery.
For more information about DGI's Phenomics Activities, see the June, 2000 issue of "Genetic
Engineering News." Article is in PDF format and requires Adobe Acrobat Reader. Go to
FREE Download Site for Adobe Acrobat Reader.
The Diogenesis® Process as an Aid for Rational Drug
Design
DGI's peptide and antibody Surrogates offer a means of obtaining information for Rational Drug
Design. Here, the critical object is to obtain the crystal structure of partner bound to partner.
From these complexes, one can deduce much of the necessary information on partner/partner
contact and biological activity as well as having a defined route to rationale design of analog
elements with agonist or antagonist activity. Although there has been much progress in structural
biology, there remains a shortage of target and partner crystal complexes. Many times this is
directly related to the difficulty of co-crystallizing protein pairs. With the completion of the
human genome project, there will be a large number of proteins lacking known partners. Many
of these will be important in various disease processes. Surrogate peptides, with agonist or
antagonist activity, offer an easy alternative for obtaining partners for co-crystallization and
subsequent Rational Drug Design.
SUMMARY
The Diogenesis® Process, through its use of diverse and random recombinant antibody and
peptide libraries, is able to select small molecule drug candidates with the attributes of effective
pharmaceuticals early in the drug discovery and development process. Linking the binding,
selectivity and activation of desired targets by Surrogates allows drug selection through the use
of Site Directed Assays and High Throughput Screening protocols. Diogenesis® uses
information about the biological characteristics of its Surrogate peptides and antibodies to
develop electronic drug discovery methods and to direct the synthesis of novel compounds. In
addition, Diogenesis® can be used to phenotype a novel gene (Phenomics) and in Rational Drug
Design. By identifying viable drug candidates early in the development process, Diogenesis®
reduces the risk of false lead optimization saving both time and money. Also, by dividing active
surfaces into their minimal hotspots, Diogenesis® allows for the identification of multiple small
molecules which, when linked together, offer orally active replacements for natural proteins.
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