Stromal cell-derived factor 1 alpha (SDF1α) is a signaling protein, capable of inducing self-healing of the heart, making it a potential treatment for cardiovascular disease – the leading cause of mortality worldwide. By activating its cognate receptor, SDF1α recruits regenerative cells to the site of injury via a series of intracellular events, including decrease in cyclic adenosine monophosphate (cAMP) concentration and increase in intracellular calcium, to result in cell migration. Clinical studies have shown that SDF1α is upregulated during acute myocardial infarction (AMI), leading to stem cell recruitment, retention, and proliferation at the infarcted site. Intracardiac injection of SDF1α following an induced AMI in murine models have shown significant improvement in cardiac functions, along with reduction in infarct size and angiogenesis. Despite its therapeutic potential, SDF1α is rapidly inactivated by the ubiquitous serine protease, dipeptidyl peptidase-IV (DPP-IV), and matrix metalloproteinase II (MMP-II), by removal of an N-terminal dipeptide (Lys-Pro) or the N-terminal pentapeptide (Lys-Pro-Val-Ser), producing truncated analogues that are far less potent and efficacious, and completely lacking their regenerative potential. We report here the design and functional characterization of SDF1α analogues employing molecular modifications to generate a potent analogue that can resist proteolytic cleavage via (i) modulation of the pKa of the N-terminal main chain amino group and (ii) using unnatural amino acid side chains to render the protein refractory to proteases, thereby making it a long-lived compound in vivo. We will report on the design, synthesis and biochemical characterization of the constructs as a starting point for further development of candidate therapeutic compounds useful for the amelioration of cardiovascular disease.

Molecular design of a protease resistant analogue of SDF1α

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.