Medicinal Chemistry Approaches to Heart Regeneration.
Because of the minimal and clearly insufficient ability of the adult heart to regenerate after ischemic injury, there is a great opportunity to identify biological mechanisms, substances, and factors that enhance this process. Hence, innovative therapeutic management of heart failure following infarction requires a paradigm shift in pharmacotherapy. Spurred by tremendous progress in the field of stem cell and cardiac biology, several attractive approaches for regeneration of lost cardiomyocytes and supporting vasculature have emerged. Research in this area focuses on restoring the hearts' original function via proliferation and differentiation of cardiac progenitor cells, proliferation of pre-existing cardiomyocytes, and reprogramming of cardiac fibroblasts. In this review, we outline these principal strategies, putative biological targets or signaling pathways and chemical agents, with a focus on small molecules, to achieve therapeutic heart regeneration. We also point out the many remaining questions and challenges, particularly for translating in vitro discoveries to in vivo application.
Department of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Dennis
D
Schade
Department of Medicinal Chemistry, Cardiovascular and Metabolic Diseases Innovative Medicines, AstraZeneca , Pepparedsleden 1, Mölndal, 43183, Sweden.
Alleyn T
AT
Plowright
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*