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INC Research and Clinical Research Institute Of Montreal | Date: 2017-03-22

The present invention relates to a specific aromatic-cationic peptide and its use in reducing the number of mitochondria undergoing mitochondrial permeability transition (MPT), or preventing mitochondrial permeability transitioning in a mammal.

Szeto H.H.,Cornell University | Schiller P.W.,Clinical Research Institute of Montreal
Pharmaceutical Research | Year: 2011

Mitochondrial oxidative stress and dysfunction have been implicated in the aging process and in numerous chronic diseases. The need for therapies that can protect and/or improve mitochondrial function is obvious. However, the development of mitoprotective drugs has been hampered by a number of challenges, and there are at present no approved therapies for mitochondrial dysfunction. This article describes the original discovery, preclinical development, and clinical development of a novel class of small peptide molecules that selectively target the inner mitochondrial membrane and protect mitochondrial function. These compounds have the potential to be a paradigm-shifting approach to the treatment of mitochondrial dysfunction, which underlies many common diseases, including cardiorenal, neurologic, and metabolic disorders. © Springer Science+Business Media, LLC 2011.

INC Research and Clinical Research Institute Of Montreal | Date: 2013-10-30

The present invention relates to a specific aromatic-cationic peptide that is useful in clinical applications such as for increasing cardiac contractility in a subject and inhibiting cardiac stunning in a subject. The peptide can also be used to enhance the preservation of a removed organ.

INC Research and Clinical Research Institute Of Montreal | Date: 2012-08-29

The invention provides a method of reducing or preventing mitochondrial permeability transitioning. The method comprises administering an effective amount of an aromatic-cationic peptide having at least one net positive charge; a minimum of four amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p_(m)) and the total number of amino acid residues (r) wherein 3p_(m) is the largest number that is less than or equal to r + 1; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p_(t)) wherein 2a is the largest number that is less than or equal to p_(t) + 1, except that when a is 1, p_(t) may also be 1.

INC Research and Clinical Research Institute Of Montreal | Date: 2015-04-29

The present invention relates to the use of a specific aromatic-cationic peptide to enhance the preservation of a removed organ.

Seidah N.G.,Clinical Research Institute of Montreal
Annals of the New York Academy of Sciences | Year: 2011

Limited proteolysis of secretory proteins is performed by one or more of the nine-membered proprotein convertase (PC) family: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9. The first seven proteinases cleave proproteins at single or pairs of basic residues in the Golgi, secretory granules, cell surface, or endosomes. These comprise neural and endocrine hormones and their release/inhibiting factors, growth factors and their receptors, and adhesion molecules. The regulated neural and endocrine PC1/3 and PC2 generate multiple peptide hormones and neuropeptides, including the family of hypothalamic-releasing/inhibiting factors. The ubiquitously expressed furin is the principal PC that processes constitutively secreted proteins. PC4 controls testicular and ovarian physiology. PC5/6 and PACE4 bind heparin sulfate proteoglycans and play critical roles during development by regulating body axis and polarity determinants. PC7 exerts unique functions in the brain. The members SKI-1/S1P and PCSK9 do not require a basic residue at the cleavage site and play major roles in the regulation of cholesterol/lipid homeostasis. In vivo studies demonstrated that PCs play major roles in health and disease states. © 2011 New York Academy of Sciences.

Seidah N.G.,Clinical Research Institute of Montreal
Methods in Molecular Biology | Year: 2011

The proprotein convertases (PCs) are secretory mammalian serine proteinases related to bacterial subtilisin-like enzymes. The family of PCs comprises nine members, PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9 (Fig. 3.1). While the first seven PCs cleave after single or paired basic residues, the last two cleave at non-basic residues and the last one PCSK9 only cleaves one substrate, itself, for its activation. The targets and substrates of these convertases are very varied covering many aspects of cellular biology and communication. While it took more than 22 years to begin to identify the first member in 1989-1990, in less than 14 years they were all characterized. So where are we 20 years later in 2011? We have now reached a level of maturity needed to begin to unravel the mechanisms behind the complex physiological functions of these PCs both in health and disease states. We are still far away from comprehensively understanding the various ramifications of their roles and to identify their physiological substrates unequivocally. How do these enzymes function in vivo? Are there other partners to be identified that would modulate their activity and/or cellular localization? Would non-toxic inhibitors/silencers of some PCs provide alternative therapies to control some pathologies and improve human health? Are there human SNPs or mutations in these PCs that correlate with disease, and can these help define the finesses of their functions and/or cellular sorting? The more we know about a given field, the more questions will arise, until we are convinced that we have cornered the important angles. And yet the future may well reserve for us many surprises that may allow new leaps in our understanding of the fascinating biology of these phylogenetically ancient eukaryotic proteases (Fig. 3.2) implicated in health and disease, which traffic through the cells via multiple sorting pathways (Fig. 3.3). © 2011 Springer Science+Business Media, LLC.

Nimesh S.,Clinical Research Institute of Montreal
Current Clinical Pharmacology | Year: 2012

Recent discovery of RNA interference (RNAi) technology for gene therapy has triggered explosive research efforts towards development of small interfering RNA (siRNA) as therapeutic modality for gene silencing. Owing to its large molecular weight (~13 kDa), polyanionic nature (~40 negative phosphate groups) and rapid enzymatic degradation, delivery of siRNA remains an unresolved issue. Hence, there arises a need of an appropriate delivery vector to overcome the intrinsic, poor intracellular uptake and limited in vitro and in vivo stability. Amongst the various non-viral delivery vectors, the application of polymeric vectors such as polyethylenimine (PEI) or its derivatives has attracted much attention due to its high transfection efficiency and ease of manipulation. PEI has been extensively investigated for DNA delivery, only recently this polymer has been employed for siRNA delivery. This review will focus on studies done on PEI to deliver siRNA, with emphasis on the targeted, self-assembled polymeric nanoparticles with promising potential to evolve as therapeutic tool in gene therapy. © 2012 Bentham Science Publishers.

Veillette A.,Clinical Research Institute of Montreal
Cold Spring Harbor perspectives in biology | Year: 2010

The signaling lymphocytic activation molecule (SLAM) family of receptors and the SLAM-associated protein (SAP) family of intracellular adaptors are expressed in immune cells. By way of their cytoplasmic domain, SLAM-related receptors physically associate with SAP-related adaptors. Evidence is accumulating that the SLAM and SAP families play crucial roles in multiple immune cell types. Moreover, the prototype of the SAP family, that is SAP, is mutated in a human immunodeficiency, X-linked lymphoproliferative (XLP) disease. In the presence of SAP-family adaptors, the SLAM family usually mediates stimulatory signals that promote immune cell activation or differentiation. In the absence of SAP-family adaptors, though, the SLAM family undergoes a "switch-of-function," thereby mediating inhibitory signals that suppress immune cell functions. The molecular basis and significance of this mechanism are discussed herein.

Chretien M.,Clinical Research Institute of Montreal | Mbikay M.,Clinical Research Institute of Montreal
Journal of Molecular Endocrinology | Year: 2016

Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chrétien and Li discovered Y-lipotropin and observed that (i) it was part of β-lipotropin (β-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was β-melanocyte-stimulating hormone (β-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active β-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of β-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families. © 2016 Society for Endocrinology Published by Bioscientifica Ltd.

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