Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity

Abstract

Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d)=0.359microM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.

Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery

“…The specificity of the observed effect was confirmed by the lack of antiproliferative properties in MDA-MB-231 breast cancer cells that are independent of the Erb-B2 growth pathway. Subsequent optimization involved the replacement of the phosphonic acid by a malonate, which docks into the pY binding pocket. − Alternative macrocyclic peptidic scaffolds devoid of the pY residue were recently reported as well …”

A Comparative Study of Short Linear Motif Compositions of the Influenza A Virus Ribonucleoproteins

“…Several reports demonstrated that peptide-mediated interference in IAV polymerase complex assembly can attenuate IAV replication [53] – [57] . SLiMs such as PDZ motif [58] , LIG_SH2_GRB2 [59] are being explored as drug targets. Since viruses have evolved to use motifs for essential functions by hijacking host proteins [60] , identification of SLiMs which mediate interactions between viral protein and host factors may provide valuable and specific information for development of motif mimetic drugs to perturb the interactions to treat virus infections [2] .…”

Targeting kinase signaling pathways with constrained peptide scaffolds

“…Further, these peptides appeared to permeate the cell membrane and phosphorylation of Her2 was found to be downregulated after treating whole cells with the Grb2 macrocycle antagonists. Multiple variations of cyclized Grb2 inhibitors were later developed with the installment of C-terminal β-functionalized allylglycines for ring-closing metathesis (RCM) (Oishi, et al, 2005), azide-alkyne cycloaddition macrocycles (Choi, et al, 2006), thioether-bridged macrocyclization (Jiang, et al, 2009) and peptide bicycles containing both head-to-tail and side chain cyclization (Quartararo, Wu, & Kritzer, 2012). Many of these peptides demonstrated improved properties including increased affinity, improved inhibition and enhanced proteolytic stability.…”