Abstract
The area of protein-protein interaction has been growing at a tremendous rate. The market is expected to reach over $50 billion by year 2010. Protein-protein interaction targeting activities are increasing and are expected to bring success in the near future. Protein-protein interactions are critical for normal and tumor cells signal transduction pathways, making them attractive targets for developing therapeutic molecules.Targeting protein-protein interactions has been challenging due to the diversity and complexity of proteins involved and the structures they form. However, the number of therapeutic molecules that have been developed against signal transduction proteins that are involved in protein-protein interactions is increasing at a steady rate.
Table of Contents
- Chapter 1 Executive Summary ................................................................... 1--1
- Chapter 2 Introduction to Protein-Protein Interaction .......................... 2--1
- Chapter 3 Cellular Events Requiring Protein-Protein Interaction......... 3--1
- Protein-Protein Interaction in Cancer Cells ......................................................... 3--5
- Protein-Protein Interaction in Insulin Pathway
.................................................... 3--8
- Alterations of Protein-Protein Interactions in Insulin Resistant States .......................3--10
- Chapter 4 Targeting PPI: Market Outlook and Analysis ........................ 4--1
- Market Segmentation for Protein-Protein Interaction Therapeutics...................... 4--3
- Targeting PPI: Opportunities and Challenges ...................................................... 4--9
- Challenges to be Faced.....................................................................................4--12
- Peptides and Peptomimetic Molecules
..............................................................4--13
- Phage Display Technology ................................................................................4--13
- Example of Peptides as PPI Inhibitors
...............................................................4--16
- Peptides Targeting HIV-1 Protease Dimerization ...................................................4--16
- Inhibitors of HSV Ribonuclease Reductase ...........................................................4--17
- Inhibitors of p53/Hdm2 Interactions ..................................................................4--17
- Small Molecule Inhibitors of PPI .........................................................................4--17
- Inhibitors of the Interaction Between Bcl-xL or Bcl-2 and Bak-BH3 Domains ..............4--18
- Inhibitors of Myc/Max Dimerization ....................................................................4--19
- Inhibitors of MMP2/Integrin 疱・ interaction ......................................................4--20
- Inhibitors of Binding of TNF-・to TNFRc1 .............................................................4--21
- Inhibitors of LFA-1/ICAM-1 Interactions ..............................................................4--21
- Inhibitors of iNOS Dimerization...........................................................................4--21
- Agonists of the EPO Receptor............................................................................4--21
- Agonist for Interaction between Human Growth Hormone and its
- Mutated Receptor ...........................................................................................4--22
- Major Examples of PPI
....................................................................................4--22
- Protein-Protein Interaction of MDM2 and p53......................................................4--22
- Protein-protein Interaction in Insulin Signaling Pathway
.....................................4--23
- Taxol: Inhibiting Protein-Protein Interaction...........................................................4--24
- Chapter 5 Exploring Chemical Space to Develop PPI Inhibitors............ 5--1
- Fragment Based Discovery Approach (FBDA) ...................................................... 5--1
- Tethering Methodology ...................................................................................... 5--2
- Competitive Antagonist of IL-2 Receptor ............................................................ 5--4
- Competitive Antagonists of B7/CD28 ................................................................ 5--5
- Allosteric Inhibitors of Nerve Growth Factor ..................................................... 5--5
- Chapter 6 Techniques to Study PPI ...........................................................
6--1
- The Yeast Two-hybrid System............................................................................. 6--1
- Yeast Two-Hybrid System .................................................................................. 6--2
- Detecting Successful Protein-Protein Interaction ............................................... 6--3
- Applications of Yeast Two-hybrid ........................................................................ 6--5
- Bioinformatics Tools for Studying PPI.................................................................
6--5
- BIND - Biomolecular Interaction Network Database ............................................... 6--6
- DIP - Database of Interacting Proteins ................................................................ 6--6
- PIM - Protein Interaction Maps ........................................................................... 6--6
- PathCalling Yeast Interaction Database ............................................................... 6--6
- MINT - Molecular Interactions Database .............................................................. 6--7
- GRID - The General Repository for Interaction Datasets ......................................... 6--7
- InterPreTS - Protein interaction prediction through tertiary structure ....................... 6--7
- STRING .......................................................................................................... 6--7
- Mammalian protein-protein interaction database (PPI) ........................................... 6--7
- InterDom - Database of Putative Interacting Protein Domains ................................. 6--8
- IntAct Project ................................................................................................. 6--8
- The Human Protein Interaction Database (HPID) ................................................... 6--8
- ADVICE - Automated Detection and Validation of Interaction by Co-Evolution ............... 6--9
- InterWeaver ................................................................................................... 6--9
- PathBLAST - Alignment of Protein Interaction Networks ......................................... 6--9
- ClusPro - Protein-protein Docking ....................................................................... 6--9
- Systems Utilized In Studying PPI.......................................................................6--10
- Aclara ...........................................................................................................6--10
- eTag・Assay System ......................................................................................6--10
- AxCell Biosciences Corp. (Now a subsidiary of Cytogen) .........................................6--10
- Databases and Tools
........................................................................................6--12
- ADVICE - Automated Detection and Validation of Interaction by Co-Evolution ..............6--12
- eFsite ...........................................................................................................6--12
- PDBjViewer ...................................................................................................6--12
- IntAct Project ................................................................................................6--12
- iPPI ...............................................................................................................6--13
- IPPRED ..........................................................................................................6--13
- PathBLAST ....................................................................................................6--14
- PEDANT - Protein Extraction, Description, and Analysis Tool ..................................6--14
- PDBSiteScan ..................................................................................................6--14
- PDGcon - Contact Prediction Server ..................................................................6--14
- PIVOT - Protein Interactions VisualizatiOn Tool .....................................................6--14
- Protein-Protein Interaction Server ......................................................................6--14
- SPIN-PP Server - Surface Properties of Interfaces -- Protein-Protein Interfaces ..........6--15
- STRING - Search Tool for the Retrieval of Interacting Genes/Proteins ......................6--15
- YETI - Yeast Exploration Tool Integrator................................................................6--15
- Web Guide for PPI............................................................................................6--16
- Databases / Data Collections............................................................................6--16
- Experimental Data ..........................................................................................6--16
- Chapter 7 Expert Opinions
.......................................................................... 7--1
- Robin Carr Ph.D., Astex Technology .................................................................. 7--1
- Stefan L蚶, Ph.D., Biacore International AB .................................................... 7--3
- James Wells, Ph.D., Sunesis Pharmaceuticals, Inc.............................................. 7--5
- Len Pagliaro, Ph.D., BioImage A/S..................................................................... 7--7
- Donny Strosberg, HYBRIGENICS ....................................................................... 7--9
- Mike Cardone, Merrimack Pharmaceuticals, Inc. ...............................................7--12
- Richard Chen, Ingenuity Systems ......................................................................7--14
- Peter van Dijken Ph.D., Pepscan Systems BV ....................................................7--16
- Kannan Gunasekaran, SAIC-Frederick, Inc. ........................................................7--17
- Chapter 8 Company Profiles
....................................................................... 8--1
- CATEGORY 1 .................................................................................................... 8--2
- Astex Technology .............................................................................................. 8--2
- Cytogen Inc. ..................................................................................................... 8--5
- Cellzome AG ..................................................................................................... 8--7
- CATEGORY 2 ...................................................................................................8--11
- Aclara Biosciences Inc......................................................................................8--11
- Biacore International AB ..................................................................................8--14
- BioImage .........................................................................................................8--17
- Dualsystems Biotech AG ..................................................................................8--18
- Hybrigenics......................................................................................................8--20
- Prolexys Phamaceuticals Inc.............................................................................8--23
- Odyssey Thera, Inc...........................................................................................8--26
- Syrrx, Inc. .......................................................................................................8--28
- CATEGORY 3 ...................................................................................................8--31
- GPC Biotech AG ...............................................................................................8--31
- Hypromatrix, Inc..............................................................................................8--36
- Protana Inc. ....................................................................................................8--41
- Panomics, Inc. .................................................................................................8--43
- Pierce Biotechnology, Inc..................................................................................8--47
- Stratagene ......................................................................................................8--49
- Chapter 9 References .................................................................................. 9--1
- Appendix: PPI Patent Analysis .............................................................. Appx--1
