Macrocyclic Control in Helix Mimetics.

The α-helix is the most commonly found natural secondary structure in proteins and is intrinsic to many protein-protein interactions involved in important biological functions. Novel peptides designed to mimic helices found in nature employ a variety of methods to control their structure. These approaches are significant due to potential applications in developing new therapeutic agents and materials. Over the years, many strategies have emerged to influence, initiate, and propagate helical content in short, synthetic peptides. Early innovations used the natural macrocycle tether of disulfide bond formation, metal-mediated or lactam group addition as a means to prompt helical formation. These examples have been applied to a host of peptides as inhibitors toward relevant diseases including cancer, viral and bacterial infection. In the most recent decades, hydrocarbon bridges to "staple" peptides across side chains or hydrogen bond surrogates in the backbone of peptides have been effective in producing biologically functional, helical peptidomimetics with non-natural elements, increased protease resistance and potency in vitro and in vivo. Modern methods expand and elaborate these, with applications of functional peptides from both synthetic and recombinant origins. Overall, efforts persist using these strategies to create peptides with great biological potential and a better understanding of the control of helical structure in protein folding.

Head-to-Tail Cyclic Peptide Inhibitors of the Interaction between Human von†Willebrand Factor and Collagen.

The development of peptide-based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug-like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein-protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation. We based our designs on two known disulfide-containing, peptide-based inhibitors of the vWF-collagen interaction. Replacing the disulfide with a head-to-tail cyclization strategy confers remarkable stability to the peptides when treated with a panel of proteases. Our peptides also showed moderate activity in our developed fluorescently linked immunosorbent assay (FLISA), similar to the most active disulfide-containing peptide. These peptides provide a springboard for future advances in exceptionally stable, active cyclic peptides as drugs.