Pharmacology of Synthetic and Biotechnology-Derived Homologues and Analogues of Heparin

Abstract

Structural and functional elucidation of the components of natural heparin has facilitated the development of several synthetic and semi-synthetic analogues of this anticoagulant drug. A chemically synthesized pentasaccharide which mimics the ATIII binding site in heparin molecule is in Phase II clinical trials for the management of post-surgical thromboembolic disorder. Several other synthetic analogues including hypersulfated lactobionic acid (Aprosu-late®) and polysulfones (GL-522) have also been developed. These agents exhibit some of the action of heparin, however their biochemical and physiologic actions are much narrower than heparin. These agents, therefore, can be used to determine the structure activity relationship in a selective manner. All of these agents exhibit varying degrees of interactions with serpins and TFPI. Chemically modified heparins (desulfated, hypersulfated) have also been developed and may have specific pharmacologic actions. The advances in biotechnology have also provided semisynthetic homologues and analogues of heparin. A bacterial polysaccharide derived product (K-5) has been molecularly optimized to mimic heparin and low molecular weight heparins. Utilizing E Coli derived polysaccharide and highly specific enzymes and chemical transformation, K-5 derived heparin homologues of varying molecular mass (5–20 kDa) have been developed. These agents exhibit surprisingly similar biochemical and pharmacologic properties in in vitro and in vivo settings when compared to heparins. This presentation will provide an overview of the current developments in both the synthetic and biotechnology areas which have provided products that can be optimized to substitute heparin and low molecular weight heparin for different indications. Such products can be optimized to exhibit better safety and efficacy index and can be especially useful in heparin compromised patients.