Selection of Peptides That Bind to SRC SH2 Domain

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$500,000.00
Award Year:
1994
Program:
SBIR
Phase:
Phase II
Contract:
n/a
Agency Tracking Number:
21950
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
Ariad Pharmaceuticals, Inc.
26 Landsdowne Street, Cambridge, MA, 02139
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
n/a
Principal Investigator:
Mark J. Zoller
(617) 494-0400
Business Contact:
() -
Research Institution:
n/a
Abstract
Mice lacking a functional c-src gene develop osteopetrosis due to a defect in bone resorption by osteoclasts (1). This evidence implicates the role of Src in osteoclast resorption activity. We aim to develop a drug that blocks the action of Src protein kinase as a potential treatment of osteoporosis. To do this, we are targeting a domain of the Src protein kinase termed SH2 (src homology 2). SH2 domains are found on a number of intracellular proteins and function as receptors for tyrosine-phosphorylated polypeptides. Our Phase I goal is to identify peptides that tightly bind to the Src SH2 domain using a technique termed "phage display". A library of pentapeptides is expressed on the surface of M13 phage fused to the gene III protein, a minor M13 coat protein. Each phage displays a single peptide sequence on its surface. The phage library is mixed with immobilized SH2 domain and non-binding phage are removed by washing. Bound phage are eluted and propagated through E. coli to produce a population of phage enriched for sequences that recognize the SH2 domain. Since SH2 domains exhibit a higher affinity for tyrosine-phosphorylated peptides versus nonphosphorylated peptides, we will use several novel approaches to phosphorylate the phage-displayed peptides. The selection cycle is repeated 5-10 times then individual phage are cloned, and the encoded peptides are sequenced. Peptides derived from the selected clones will be synthesized and tested for binding to Src SH2 domain.

* information listed above is at the time of submission.

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