6685 Angew. Chem. Int. Ed. 2005, 44, 6685–6689 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim variety of protein–protein [3] and protein–membrane interactions.[4] Their semirigid structures and their adjustable lengths mean that they provide excellent starting points for the elaboration of protein mimics that might be difficult to design based on small-molecule scaffolds. Here we describe the design of aryl amide oligomers that compete for heparin–protein interactions. Heparin, a linear and highly sulfated polysaccharide, is a crucial component in a variety of biological processes mediated by specific heparin–protein interactions including blood coagulation, viral infection, and cell growth. Heparin has become a commonly used clinical anticoagulant to prevent and treat thrombotic diseases.[5, 6] However, bleeding complications including hemorrhage and heparin-induced thrombocytopenia (HIT), which is a common immune-mediated disorder, are major adverse effects associated with heparin therapy.[7] Therefore, frequent coagulation monitoring may be necessary to minimize the risk of life-threatening hemorrhages resulting from an overdose, while at the same time maximizing the anticoagulant efficacy. Low-molecular-weight (LMW) heparins, like unfractionated (UF) heparin, consist of repeating units of l-iduronic acid and d-glucosamine (Scheme 1a). LMW heparins have resolved some of the problems associated with UF-heparin use, in that they have a more predictable dose response, an improved bioavailability, and a longer half-life.[8] Protamine is used extensively as a clinical heparin antidote to neutralize the anticoagulation function of heparin following cardiovascular surgery [9] but it is not prescribed for use with LMW-heparin therapy. Protamine treatment can also cause several side effects mediated by nonimmunologic and immunoglobulin-mediated pathways.[10] Thus, much safer and more effective agents for neutralizing the anticoagulant function of heparin are currently of great interest. The interaction between heparin and antithrombin, a plasma serine proteinase inhibitor that is the major inhibitor of the coagulation cascade, facilitates a conformational change in antithrombin. This conformational change accelerates inhibition of coagulation factors such as thrombin and factor Xa.[11, 12] Through X-ray crystallographic analysis of the antithrombin–pentasaccharide complex [13, 14] and several studies of site-directed mutagenesis of antithrombin,[15, 16] it has been shown that the negatively charged pentasaccharide binds to the basic amino acids (lysine and arginine) of antithrombin.

Furthermore, by comparing various heparin-binding proteins, Cardin and Weintraub classified two consensus sequences responsible for binding, XBBXBX and XBBBXXBX, where B is a basic residue and X is any other amino acid. It was suggested that these sequence motifs fold along one face of an α helix or β sheet.[17] Most heparin-binding sites have a bipolar structure, in which the basic amino acids are facing one side; neutral or lipophilic amino acids generally face the opposite side, regardless of the secondary structure.[18] A few medium-sized peptides such as protamine analogues,[10, 19] antithrombin-derived peptides,[20] and polyarginine peptides,[21] have been reported as potent heparin antidotes. Small-molecule inhibitors of heparin may alleviate complications associated with peptide-based heparin antidotes, such as proteolytic stability, distribution, and difficulty of scale-up. We have previously reported the synthesis of amphiphilic arylamide oligomers that mimic the biological properties of antimicrobial peptides and proteins.[4] Herein …