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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.

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.

Nimesh S.,Clinical Research Institute of Montreal
Recent Patents on DNA and Gene Sequences | Year: 2012

Small interfering RNAs (siRNAs) are rapidly emerging as new therapeutic tools for the treatment of some of the deadly diseases such as cancer. However, poor cellular uptake and instability in physiological milieu limit its therapeutic potential, hence there arises a need of a delivery system which can efficiently and repeatedly deliver siRNA to the target cells. Nanoparticles have shown immense potential as suitable delivery vectors with enhanced efficacy and biocompatibility. These delivery vectors are usually few nanometers in size, which not only protects siRNA against enzymatic degradation but also leads to tissue and cellular targeting. Nanoparticles prepared from various cationic polymers like polyethylenimine, and chitosan have been largely exploited as they bear several advantages such as, ease of manipulation, high stability, low cost and high payload. This review summarizes some of the recent patents on siRNA delivery employing polymer or lipid-based nano-vectors for therapeutic applications. © 2012 Bentham Science Publishers.

Schiller P.W.,Clinical Research Institute of Montreal | Schiller P.W.,University of Montreal
Life Sciences | Year: 2010

Strategies for the design of bi- or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi- or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt1[DALDA] with triple action as a μ opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed μ opioid agonist/δ opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a μ opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented. © 2009 Elsevier Inc.

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.

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