Oligopeptides derived from autophosphorylation sites of EGF receptor suppress EGF-stimulated responses in human lung carcinoma A549 cells.

Epidermal growth factor (EGF) receptor plays a crucial role in the biology of human cancer, and is a highly appropriate target for anticancer agents. We have previously designed oligopeptides containing the amino acid sequences around autophosphorylation sites of EGF receptor to identify a specific inhibitor of this receptor. We found that Ac-ENAEYLR-NH(2) and Ac-NYQQN-NH(2) suppressed phosphorylation of purified EGF receptor in a non-ATP-competitive manner whereas Ac-QNAQYLR-NH(2) and Ac-DYQQD-NH(2) caused inhibition in an ATP-competitive manner.

A synthetic cell-penetrating peptide antagonizing TrkA function suppresses neuropathic pain in mice.

Nerve growth factor (NGF) and its high-affinity receptor, TrkA, are one of the targets in the production of new drugs for the treatment of neuropathic pain. NGF contributes to both the initiation and maintenance of sensory abnormalities after peripheral nerve injury. This study examined the effects of IPTRK3, a new synthetic cell-penetrating peptide that antagonizes TrkA function, on neuropathic pain in mice.

Synthetic pentapeptides inhibiting autophosphorylation of insulin receptor in a non-ATP-competitive mechanism.

In an attempt to develop non-ATP-competitive inhibitors of the autophosphorylation of IR, the effects of the synthetic peptides, Ac-DIY(1158)ET-NH(2) and Ac-DY(1162)Y(1163)RK-NH(2), on the phosphorylation of IR were studied in vitro. The peptides were derived from the amino-acid sequence in the activation loop of IR. They inhibited the autophosphorylation of IR to 20.

Effect of synthetic cell-penetrating peptides on TrkA activity in PC12 cells.

As TrkA, a high-affinity receptor of nerve growth factor (NGF), is a potential target for relieving uncontrolled inflammatory pain, an effective inhibitor of TrkA has been required for pain management. To identify a specific inhibitor of TrkA activity, we designed cell-penetrating peptides combined with amino-acid sequences in the activation loop of TrkA to antagonize tyrosine kinase activity. To select a peptide inhibiting TrkA activity, we examined the effect of cell-penetrating peptides on tyrosine kinase activity of recombinant TrkA in vitro and studied their effects on NGF-stimulated neurite outgrowth and protein phosphorylation in PC12 cells.

Inhibition of autophosphorylation of epidermal growth factor receptor by a small peptide not employing an ATP-competitive mechanism.

Previously we found that short peptides surrounding major autophosphorylation sites of EGFR (VPEY(1068)INQ, DY(1148)QQD, and ENAEY(1173)LR) suppress phosphorylation of purified EGFR to 30-50% at 4000 microM. In an attempt to improve potencies of the peptides, we modified the sequences by substituting various amino acids for tyrosine or by substituting Gln and Asn for Glu and Asp, respectively. Among the modified peptides, Asp/Asn- and Glu/Gln-substitution in DYQQD (NYQQN) and ENAEYLR (QNAQYLR), respectively, improved inhibitory potencies.

Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro.

1. Inhibition of uncontrolled epidermal growth factor receptor (EGFR) is one of the approaches for the treatment of breast and lung cancers. We designed oligopeptides consisting of amino-acid sequences of the major (Y1068, Y1148, and Y1173) and minor (Y992) autophosphorylation sites of EGFR.