Role of Glycosylation in Developing Anti-cancer Therapeutics

Membrane embedded proteins are the key players in cancerous cells [1]. Almost all of the membrane proteins are glycosylated with sugar moieties (glycans) [2]. These attached glycans are known to play crucial roles in the structure, function and dynamics of the membrane proteins [3]. However, the atomistic mechanism behind these roles and their potential implementation in efficient anti-cancer drug design are poorly studied [3]. Here atomistic molecular dynamics simulations were used to investigate the role of attached glycans in the ligand binding of the Epidermal Growth Factor Receptor (EGFR) that is a tyrosine kinase associated with several cancers [4]. Auto-inhibited monomeric form of EGFR becomes untethered by binding of the growth factors to its extracellular domain [5]. The interaction between two untethered monomers forms the back-to-back dimeric construct, known to be the active form of EGFR [6]. Several antibodies are designed to inhibit EGFR by binding to the glycosylated extracellular domain [5, 7-9]. It was shown that glycosylation promotes binding affinity of EGFR for the growth factors by stabilizing the growth factor binding site and facilitates dimerization by maintaining the dimeric interfaces [3]. Glycosylation also plays various roles in the binding of antibodies to different epitopes of the EGFR extracellular domain [3]. Glycosylation seems to affect the binding affinity of monoclonal antibody 806 (mAb806) to EGFR by exposing a cryptic pocket in the extracellular domain. These findings could lead to efficient drug design for membrane proteins involved in cancer and could be expanded by designing glycan-based antibodies functioning with the glycan-glycan interactions between the target protein and the drug in cancerous cells.

Keywords:

Glycosylation , Monoclonal antibody