Mathematically Designed Synthetic Polypeptide Analog of Stromal Cell-Derived Factor 1alpha Functions as a Superpotent Neovasculogenic Agent for Treating Myocardial Ischemia
Y. Joseph Woo MD, William Hiesinger MD, Jose Manuel Perez-Aguilar BS
Jeffrey G. Saven PhD
University of Pennsylvania, Phildelphia, Pennsylvania, USA.
Abstract:
The native angiogenic repair machinery for ischemically-injured myocardium consists primarily of the stromal cell-derived 1alpha (SDF) chemokine mobilization of bone marrow derived endothelial progenitor stem cells. Although this native process is insufficiently robust to revascularize major infarcts, exogenous delivery of recombinant SDF is effective. Unfortunately, recombinant SDF is bulky, unstable, and very costly, thus hampering clinical applicability. We utilized computational protein design to engineer a truncated SDF polypeptide analog that preserved the CXCR4 receptor binding and activation N-terminus as well as the extracellular stabilization C-terminus. These were joined with specific linker amino acids to satisfy spatial restraints and minimize conformational flexibility, generating an optimized three-dimensional configuration. In vitro testing of EPC mobilization potential demonstrated significantly enhanced chemokinesis compared to both saline control and recombinant SDF. CXCR4 receptor activation was likewise more effectively augmented by this construct. In vivo experimentation in a murine coronary artery ligation model of heart failure revealed that this engineered polypeptide was highly effective in inducing angiogenesis and improving cardiac function. This novel, mathematically-designed SDF polypeptide analog offers great promise for further translational investigation and potential clinical therapeutics.
