Design, Selection and Binding Mechanism of Bivalent Miniproteins Targeting Human Thrombin
Multilvalent molecular designs have emerged as an important tool for protein engineering and drug discovery complementary to the traditional methods of medicinal chemistry and recombinant antibody technology. Like antibodies, this new generation of molecules is particularly suited for the inhibition of difficult pharmaceutical targets such as protein-protein interactions. Unlike antibody engineering, the design of effective multivalent (or minimally bivalent) molecules is still wrought with trial and error, especially with regard to the selection of individual binding moieties and the choice of linking strategies. Using the thrombin system as an example, we aim to evolve a general approach for the design of protein-targeting bivalent polypeptides. Our design scheme involved the selection of binding moieties through screenings of relatively unsophisticated libraries, which often yield low-affinity, fast-dissociating hits. Through bivalency, however, we showed that these...
KeywordsActive Site Inhibitor Bivalent Binding Linker Moiety Avidity Effect Undesirable Protein