Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death, and generate most of the cell’s energy. Mitochondria maintain their homeostasis by dynamic (fission and fusion) and quality control mechanisms, including mitophagy, the removal of damaged mitochondria that is mediated mainly by the Pink1/Parkin pathway. Pink1 is a serine/threonine kinase which regulates mitochondrial function, hitherto many molecular mechanisms underlying Pink1 activity in mitochondrial homeostasis and cell fate remain unknown. Peptides are vital biological mediators that demonstrate remarkable potency, selectivity, and low toxicity, yet they have two major limitations, low oral bioavailability and poor stability. Herein, we rationally designed a linear peptide that targets Pink1 and, using straightforward chemistry, we developed molecular probes with drug-like properties to further characterize Pink1. Initially, we conjugated a cell-penetrating peptide and a cross-linker to map Pink1’s 3D structure and its interaction sites. Next, we conjugated a fluorescent dye for cell-imaging. Finally, we developed cyclic peptides with improved stability and binding affinity. Overall, we present a facile approach to converting a non-permeable linear peptide into a research tool possessing important properties for therapeutics. This is a general approach using straightforward chemistry that can be tailored for various applications by numerous laboratories.

: : Cardiovascular diseases (CVDs) are the leading global cause of death, accounting for more than 17.6 million deaths per year in 2016, a number that is expected to grow to more than 23.6 million by 2030. While many technologies are currently under investigation to improve the therapeutic outcome of CVD complications, only few medications have been approved. Therefore, new approaches to treat CVD are urgently required. Peptides regulate numerous physiological processes, mainly by binding to specific receptors and inducing a series of signals, neurotransmissions or the release of growth factors. Importantly, peptides have also been shown to play an important role in the circulatory system both in physiological and pathological conditions. Peptides, such as angiotensin II, endothelin, urotensin-II, urocortins, adrenomedullin and natriuretic peptides have been implicated in the control of vascular tone and blood pressure as well as in CVDs such as congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Hence it is not surprising that peptides are becoming important therapeutic leads in CVDs. This article will review the current knowledge about peptides and their role in the circulatory system, focusing on the physiological roles of natriuretic peptides in the cardiovascular system and their implications in CVDs.

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