Development of New Protein Capture Technologies

Overview

Fundamental understanding of normal and disease processes depends on further exploration of cell and systems biology which in turn will depend on the ability to fully define and characterize protein structure, function and interaction. Well characterized and validated capture reagents will be key in proteomic platforms for the understanding, prevention, early detection, and treatment of many diseases. A number of existing techniques have resulted in the development of reagents (antibodies) capable of specific and selective binding sites in proteins or protein complexes. In addition, a number of technologies of great potential are emerging which involve insertion of combinatorial binding sites in alternate (non-antibody) protein scaffolds, synthesis of oligomers (RNA and DNA aptamers, oligo- and polypeptides of either natural and unnatural amino acids, and hybrids of these forms), and small organic molecules whether natural (biotin, tetrodtoxin, resiniferatiotoxin, lectin binding carbohydrates side chains) or entirely synthesis (substract-based enzyme inhibitors). Considerable progress has been made in the development, refinement and application of the technologies and approaches, yet no single approach or technology offers the capability to achieve the goal of generating a highly diverse library of capture reagents that can be used on high through-put assays.

The goal of this NIH Roadmap Initiative is to promote the development of new high through-put technologies for the generation of libraries of diverse small molecules that specifically or selectively recognize, bind and “capture” human proteins or that distinguish among the natural variants [splice variants, co- and post-translational modifications (by glycosylation, phophorylation, acylation, oxidation, etc.)] of a single protein. Two categories of capture reagents are envisioned: 1) those that will recognize and capture all apo- (unmodified) proteins, and 2) those that will distinguish among the co-and post-translational modifications of a single protein. The binding specificity/selectivity will be determined by high throughput screening such as array-type and/or FACS analysis. Future usage is envisioned to include analysis of scale-up potential target range to bind a full repertoire of proteins, ability to recognize protein complexes and metabolic pathways, ability to perturb/block the function of the target protein, and utility for cellular, organ, body visualization and diagnostics.

This Roadmap Initiative will complement ongoing efforts within NIH Institutes and Centers related to conventional antibody technologies. Additionally, this initiative relates to ongoing Roadmap programs in Molecular Libraries, Nanomedicine and Structural Biology, yet is distinct in terms of its highly focused and targeted objectives.

The URL for the NIH Roadmap Web site is nihroadmap.nih.gov. Support for the NIH Roadmap and its initiatives is provided by the NIH Common Fund, and teams of staff across the NIH direct and oversee each initiative. Scientific investigators who wish to discuss Grants and Funding Opportunities should contact Dr. Daniel Gallahan, Development of New Protein Capture Technologies Project Team Leader (gallahad@mail.nih.gov). For information about the role of the Office of Portfolio Analysis and Strategic Initiatives (OPASI) in this program, contact Dr. Eleni Kousvelari OPASI Program Director (Kousvelarie@mail.nih.gov). Further information about the NIH can be found at its Web site: www.nih.gov.

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