Polymers have traditionally taken a back seat to small molecules in the pharmaceutical industry: they have been used as secondary components that are no more than packing material for the 'active' molecules. Our goal is to perform the initial studies intended to lead eventually to polymers being the active molecules: polymers as drugs. We have recently synthesized a family of polymers that have sialic acid (a sugar) tethered to side chains. These 'poly(sialic acids)' bind with ultrahigh (picomolar) affinity to the surface of flu virus. In so binding, the polymer prevents this virus from binding to surface cells in the throat and mouth, and therefore is intended to prevent disease. We wish to demonstrate that this strategy is effective for flu virus, then wish to show that polyvalency is in fact a general strategy in drug design. We have varied the chemical structure of the backbone of the polymer to optimize empirically the polymer's effectiveness in preventing this virus-cell adhesion. Several interesting aspects of this work are reported: we developed a new tool based on optical tweezers to measure these ultrahigh affinities; we identified a novel mechanism of action (steric stabilization) in these anti-adhesives that is particular to polymers and is new to the drug industry; we continue to rationalize the empirical relationships between structure and effectiveness of the polymers in terms of polymer structure and dynamics. The ultimate goal of our research program is to understand the physicochemical factors that influence the ability of the polymer both to bind tightly to the surface of the virus, and to stabilize the surface of the virus sterically, and thereby, to design and synthesize molecules that effectively inhibit the interaction of any two complementary biological surfaces.
References:
Mammen, M.; Helmerson, K.; Kishore, R.; Choi, S-K.; Phillips, W.D. and Whitesides, G.M. "Optically Controlled Collisions of Biological Objects to Evaluate Potent Polyvalent Inhibitors of Virus-Cell Adhesion," Chem. and Biol. 3, 757-763, 1996.
Choi, S-K.; Mammen, M. and Whitesides, G.M. "Monomeric Inhibitors of Influenza Neuraminidase Enhance the Activities of Polyacrylamides Presenting Multiple C-Sialoside Groups in Inhibiting Hemagglutination," Chem. and Biol. 3, 97-105, 1996 [Reviewed in Chemical and Engineering News March 1, 1996; Chemistry and Industry March 1996; New Scientist March 16, 1996].
Sigal, G.B.; Mammen, M. and Whitesides, G.M. "Polyacrylamides Bearing Pendant a-Sialoside Groups Strongly Inhibit Agglutination of Erythrocytes by Influenza Virus: The Strong Inhibition Reflects Enhanced Binding Through Cooperative Polyvalent Interactions," J. Am. Chem. Soc. 118, 3789-3800, 1996.1. F. Ilmain, T. Tanaka and E. Kokufuta, "Volume Transition in a Gel Driven by Hydrogen Bonding," Nature 349, 6308, 400-401 (1991).