Rajesh Sankaranarayanan

Heterobivalent Ligands Crosslink Multiple Cell-Surface Receptors ― A Step Towards Personal Medicine

Introduction Effective treatment of tumor malignancies depends upon identifying targets – molecular markers that differentiate cancer cells from healthy cells. Current cancer therapies involve targeting either differential metabolism, especially nucleic acid biosynthesis pathways, or overexpressed specific gene products. We propose an alternative approach – to specifically target combinations of cell-surface receptors using heteromultivalent ligands (htMVLs). We envision that a three cell-surface protein combination that is expressed on a cancer cell but not on a normal cell could be targeted with heteromultivalent ligands displaying cognate binding motifs of weak affinities. These constructs should bind with high avidity and specificity to cancer population in vivo [1, 2]. As a proof-of-concept, we have synthesized series of heterobivalent constructs of MSH, CCK and -opioid receptors (Fig. 1). The constituent binding motifs in these constructs were moderately potent (see Fig. 1 legend) and were connected via a semi-rigid poly(Pro-Gly) linker flanked by flexible polyethylene glycol based PEGO chains.