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Peptide bicycles that inhibit the Grb2 SH2 domain.

ABSTRACT: Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples to produce peptide bicycles with higher affinity, selectivity, and resistance to degradation. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homology 2 (SH2) domain of growth-factor-bound protein 2 (Grb2). Several homodetic peptide bicycles were synthesized entirely on-resin with high yields. Two rounds of iterative design produced peptide bicycle BC1, which is 60 times more potent than G1 and 200 times more selective. Moreover, BC1 is completely intact after 24 hours in buffered human serum, conditions under which G1 is completely degraded. Our peptide-bicycle approach holds promise for the development of selective inhibitors of SH2 domains and other phosophotyrosine (pTyr)-binding proteins, as well as inhibitors of many other protein-protein interactions.

SUBMITTER: Quartararo JS

PROVIDER: S-EPMC3516885 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Peptide bicycles that inhibit the Grb2 SH2 domain.

Quartararo Justin S JS Wu Pianpian P Kritzer Joshua A JA

Chembiochem : a European journal of chemical biology 20120611 10

Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples to produce peptide bicycles with higher affinity, selectivity, and resistance to degradation. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homolog ...[more]

PMID: 22689355

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Project description:Structures of the Grb2 SH2 domain complexed with a series of pseudopeptides containing flexible (benzyl succinate) and constrained (aryl cyclopropanedicarboxylate) replacements of the phosphotyrosine (pY) residue in tripeptides derived from Ac-pYXN-NH(2) (where X = V, I, E and Q) were elucidated by X-ray crystallography. Complexes of flexible/constrained pairs having the same pY + 1 amino acid were analyzed in order to ascertain what structural differences might be attributed to constraining the phosphotyrosine replacement. In this context, a given structural dissimilarity between complexes was considered to be significant if it was greater than the corresponding difference in complexes coexisting within the same asymmetric unit. The backbone atoms of the domain generally adopt a similar conformation and orientation relative to the ligands in the complexes of each flexible/constrained pair, although there are some significant differences in the relative orientations of several loop regions, most notably in the BC loop that forms part of the binding pocket for the phosphate group in the tyrosine replacements. These variations are greater in the set of complexes of constrained ligands than in the set of complexes of flexible ligands. The constrained ligands make more direct polar contacts to the domain than their flexible counterparts, whereas the more flexible ligand of each pair makes more single-water-mediated contacts to the domain; there was no correlation between the total number of protein-ligand contacts and whether the phosphotyrosine replacement of the ligand was preorganized. The observed differences in hydrophobic interactions between the complexes of each flexible/constrained ligand pair were generally similar to those observed upon comparing such contacts in coexisting complexes. The average adjusted B factors of the backbone atoms of the domain and loop regions are significantly greater in the complexes of constrained ligands than in the complexes of the corresponding flexible ligands, suggesting greater thermal motion in the crystalline state in the former complexes. There was no apparent correlation between variations in crystal packing and observed structural differences or similarities in the complexes of flexible and constrained ligands, but the possibility that crystal packing might result in structural variations cannot be rigorously excluded. Overall, it appears that there are more variations in the three-dimensional structure of the protein and the ligand in complexes of the constrained ligands than in those of their more flexible counterparts.

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Peptide bicycles that inhibit the Grb2 SH2 domain.

Publications

Peptide bicycles that inhibit the Grb2 SH2 domain.

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