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Design and characterization of non-phosphopeptide inhibitors for Src family SH2 domains.

Abstract：

:The development of novel non-phosphopeptide inhibitors for the Src family SH2 domain is described. Several commercially available hydroxyl aromatic acids have been appended off the N-terminus of pYEEIE and the potent phosphopeptide inhibitors of GST-Lck-SH2 were identified via ELISA. The most potent inhibitor, caffeic acid-pYEEIE, exhibited approximately 30-fold more binding activity than Ac-pYEEIE. Non-phosphopeptides were synthesized by replacing phosphotyrosine of caffeic acid-pYEEIE with tyrosine or 3,4-dihydroxyphenylalanine (DOPA). Caffeic acid-DOPA-EEIE that did not contain phosphotyrosine and its isosteres exhibited less than 20 times decreased binding affinity for GST-Lck-SH2 than Ac-pYEEIE. Moreover, it had a similar binding affinity for the GST-Lck-SH2, GST-Src-SH2, and GST-Fyn-SH2 domains. This study showed that the pY-1 positions of the phosphopeptide inhibitors and of the non-phosphopeptide inhibitors played an important role in the binding for the SH2 domain and that the non-phosphopeptide inhibitor must be a new lead in the development of SH2 inhibitors.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Park SH,Won J,Lee KH

doi

10.1016/s0960-894x(02)00523-1

subject

Has Abstract

pub_date

2002-10-07 00:00:00

pages

2711-4

issue

19

eissn

0960-894X

issn

1464-3405

pii

S0960894X02005231

journal_volume

12

pub_type

杂志文章

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