The epidermal growth factor receptor (EGFR) is a high  affinity cell surface tyrosine kinase  receptor(RTK), transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. ErbB family of receptors consists of four closely related receptors: HER1, HER2 (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). These structurally related receptors are single chain transmembrane glycoproteins consisting of an extracellular ligand-binding ectodomain, a transmembrane domain and an intracellular tyrosine kinase domain. The extracellular ectodomain contains four subdomains called domain I, II, III and IV. When the ligand binds between subdomains I and III of the ectodomain, it undergoes a conformational change and homodimerizes and/or heterodimerizes with other EGFR family members. Receptor dimerization is essential for activation of the intracellular tyrosine kinase domain and phosphorylation of the C-terminal tail for the downstream signalling.1 
ErbB family members can be activated by 13 known ligands, which include EGF, transforming growth factor alpha (TGF-?), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), epiregulin (EPR), epigen (EPG) and neuregulins 1–6 (NRG) . Among these ligands, EGF, TGF-?, AR, BTC and EPR bind specifically to HER1. A characteristic feature of HER2 is its inability to bind to any of the known ligands of the EGFR family. However, recent studies have shown that HER2 is regulated and stabilised by MUC4 mucin further potentiating HER2 and its downstream signalling in pancreatic and ovarian cancer 12, 13. Absence of ligand binding property of HER2 mandates that its activation occurs only as a consequence of a heterodimer formation with EGFR, HER3 or HER4 to generate high-affinity complexes for different ligands. 

Role of EGFR in cancer:

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Ligand-independent receptor activation occurs in some cases, that display forms of the EGFR and HER that have a deletion of the extracellular domain that result in constitutive receptor activation 5, 6. Overexpression of the urokinase-type plasminogen activator receptor also results in ligand-independent activation of the EFGR via association ?5?1 integrin 7. Finally, ligand-independent receptor activation occurs as a result of cellular stresses, such as radiation, which silence phosphatases that antagonize the receptor kinase activity and many reasons unknown, thereby shifting the equilibrium of basal phosphorylation toward the activated state. Deregulation  of EGFR by over-expression or constitutive activation promotes tumor processes including angiogenesis and metastasis and is associated with poor prognosis in many human malignancies including glioma, lung and breast cancer 1, 2. The prevalence of this receptor in well-established cancers has elicited several studies and discoveries leading to the generation of multiple monoclonal antibodies (as cetuximab and panitumumab for the treatment of colorectal cancer, NSCLC, and squamous cell carcinoma of the head and neck) that bind to the extracellular domain of EGFR, and small-molecule inhibitors (as gefitinib, erlotinib and lapatinib for the treatment of NSCLC, breast and pancreas cancers) that compete with ATP for binding to the tyrosine kinase domain of the receptor2,16,18-20. .The treatment of tumor cells with these agents affects many of the intracellular pathways that are essential for cancer development and progression. However, patients receiving these treatments often show primary or acquired resistance to the small molecule inhibitors and the short biological half-life and high cost of antibody-based inhibitor production has led researchers to work on alternative methods to design novel inhibitors like peptide inhibitors.
The project proposal is aimed to design and synthesize novel non-canonical consisting peptide inhibitors against EGFR using Computational Protein Design (CPD) .

Significance of designing peptide inhibitors against sEGFR
The crucial involvement of EGFR activation in cell proliferation and differentiation explains its direct association with the development of human cancer. 
EGFR ,in the closed conformation possess  auto-inhibition activity  between domain-II and domain-IV and when EGFR interacts with the ligand, it opens and forms the homo or a heterodimer with another EGFR receptor9,14,but in abnormal conditions this auto-inhibition activity does not work and leads to tumour formation.This over-expression can be inhibited by using antibody or ligand inhibitors. Though some antibody inhibitor such as Cetuximab targets near the ligand-binding site of domain-III and hinders the ligand-receptor interaction many other inhibitors are also present but there is no known peptide based inhibitors target ligand binding site of EGFR. Targeting this surface presents a good prospect for developing novel and potent competitive inhibitors for EGFR, HER3 and HER4. It will help to invent novel peptide inhibitors against receptor targets.