Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors

Ramos‐Molina, Bruno; Lick, Adam N.; Shirazi, Amir Nasrolahi; Oh, Donghoon; Tiwari, Rakesh; El-Sayed, Naglaa Salem; Parang, Keykavous; Lindberg, Iris

doi:10.1371/journal.pone.0130417

Cited by 30 publications

(18 citation statements)

References 51 publications

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“…Although the delivery of this nonapeptide presents difficulties, it has provided the bases for potential modifications that led to promising newly formulated inhibitors [52] (figure 1B). More recently, cyclic peptides constructed using arginines and variable side chains demonstrated inhibitory activity against furin, combined with an enhanced ability for cell penetration [53]. …”

Section: Paralyzing the Master Switches: Inhibition Of Pcsmentioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents has also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.

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Section: Paralyzing the Master Switches: Inhibition Of Pcsmentioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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“…Proprotein convertase consists of a family of proteolytic enzymes that cleave inactive proteins, including MMPs into an active state. Poly-arginine peptides and other CARPs are potent inhibitors of convertases, such as furin, PC1, PC4, PC5/6, and PC7 (272)(273)(274)(275)(276).…”

Section: Inhibition Of Matrix Metalloproteinase Activation and The Prmentioning

confidence: 99%

Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

2020

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There are virtually no clinically available neuroprotective drugs for the treatment of acute and chronic neurological disorders, hence there is an urgent need for the development of new neuroprotective molecules. Cationic arginine-rich peptides (CARPs) are an expanding and relatively novel class of compounds, which possess intrinsic neuroprotective properties. Intriguingly, CARPs possess a combination of biological properties unprecedented for a neuroprotective agent including the ability to traverse cell membranes and enter the CNS, antagonize calcium influx, target mitochondria, stabilize proteins, inhibit proteolytic enzymes, induce pro-survival signaling, scavenge toxic molecules, and reduce oxidative stress as well as, having a range of anti-inflammatory, analgesic, anti-microbial, and anti-cancer actions. CARPs have also been used as carrier molecules for the delivery of other putative neuroprotective agents across the blood-brain barrier and blood-spinal cord barrier. However, there is increasing evidence that the neuroprotective efficacy of many, if not all these other agents delivered using a cationic arginine-rich cell-penetrating peptide (CCPPs) carrier (e.g., TAT) may actually be mediated largely by the properties of the carrier molecule, with overall efficacy further enhanced according to the amino acid composition of the cargo peptide, in particular its arginine content. Therefore, in reviewing the neuroprotective mechanisms of action of CARPs we also consider studies using CCPPs fused to a putative neuroprotective peptide. We review the history of CARPs in neuroprotection and discuss in detail the intrinsic biological properties that may contribute to their cytoprotective effects and their usefulness as a broad-acting class of neuroprotective drugs.

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“…Rather, it has been proposed that at least one mechanism by which these arginine-rich peptides exert their neuroprotective effects is by inducing the internalization of neuronal cell surface structures, as a result of endocytosis [10,12,13], thereby reducing the effects of excitotoxicity and its down-stream neuro-damaging signaling pathways. Additionally, poly-arginine and other cationic arginine-rich peptides are potent inhibitors of proprotein convertase enzymes, including furin [14], a ubiquitously expressed calcium-dependent convertase involved in both physiological and pathological processes such as matrix metalloproteinase activation.…”

Section: Expert Review Of Neurotherapeuticsmentioning

confidence: 99%