Abstract

Harvesting Nature’s Diversity of Glycosaminoglycans for Therapy

Umesh Desai, Professor, Virginia Commonwealth University

Glycosaminoglycans (GAGs) are unusual biopolymers that interact with a large number of human proteins. Many of these interactions are important in human biology, especially thrombosis, cancer, inflammation, and immune response. Yet, very few GAGs have reached the clinic. Those that are used as drugs include heparin, low molecular weight heparin (e.g., enoxaparin) and fondaparinux. The primary reason for this state-of-art is that the interaction of biopolymers with proteins has been difficult to ascertain as specific. We have developed Combinatorial Virtual Library Screening (CVLS) technology to identify new naturally existing GAG sequences that may possess biological activity. Our CVLS technology identifies small sequences, which can be synthesized or isolated, that bind to distinct proteins with high selectivity. The talk will present results on the discovery of a heparan sulfate hexasaccharide from a library of 46,656 natural sequences that selectively binds and activates heparin cofactor II (HCII), a plasma serpin, for accelerated inhibition of thrombin, a pro-coagulant protease. Similar results could theoretically be achieved with any protein – GAG system of interest with respect to drug discovery.