Synthesis and in vitro opioid activity profiles of DALDA analogues

Schiller, Peter W.; Nguyen, Thi M.‐D.; Berezowska, Irena; Dupuis, Sébastien; Weltrowska, Grazyna; Chung, Nga N.; Lemieux, Carole

doi:10.1016/s0223-5234(00)01171-5

Cited by 153 publications

(197 citation statements)

References 16 publications

Supporting

Mentioning

187

Contrasting

Order By: Relevance

“…With respect to cellular location of SS peptides, confocal laser scanning microscopic studies of intestinal epithelial cells, neuronal cells, and HeLa cells demonstrated localization to the mitochondrion (21). Such mitochondrial targeting also was observed by uptake studies using liver and brain mitochondria (21,23). Therefore, it seems that mitochondria targeting of these SS peptides can be generalized to most, if not all, cell types.…”

Section: Discussionmentioning

confidence: 75%

Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function

Thomas¹,

Stauffer²,

Zhao

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Apoptotic cell death is a defined pathway for islet cell demise, and mitochondrial dysfunction contributes to islet cell apoptosis. The hypothesis that the novel peptide D-Arg-2, 6-dimethyltyrosine-Lys-Phe-NH 2 (SS-31), previously shown to target inner mitochondrial membrane and prevent oxidative damage of neuronal cells and other cell types, optimizes pancreatic islet isolation and improves posttransplantation function in recipients with diabetes was investigated. Herein is demonstrated that SS-31 readily penetrates intact mouse islets, preserves mitochondrial polarization, reduces islet cell apoptosis, and increases islet cell yield. Optimization of islet isolation is demonstrable after SS-31 pretreatment of islet (pancreas) donor mice and with the addition of SS-31 to reagents that are used in the isolation of mouse islets. The supplementation of in vitro culture medium with SS-31 reduced islet cell apoptosis and increased the viability of human islets, as ascertained by dual-parameter flow cytometry analysis. In a stringent marginal islet cell mass transplantation model (200 mouse islets transplanted under the renal capsule of syngeneic diabetic mice) and using islets that were derived from old mice (>24 wk), SS-31 treatment was associated with prompt and sustained normoglycemia, whereas the untreated islet graft recipients remained diabetic. Our data suggest a novel strategy to optimize islet isolation and reduce the need for multiple pancreata to achieve insulin independence in the recipient with type 1 diabetes. Because SS-31 was effective with "extended" islet donors, it is hypothesized that the antioxidant SS-31 may serve to increase the pool of eligible organ donors.

show abstract

Section: Discussionmentioning

confidence: 75%

Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function

Thomas¹,

Stauffer²,

Zhao

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…RNAiMAX reagent and stealth RNAi for RNA knockdown experiments were purchased from Invitrogen. The mitochondria-specific ROS scavenger peptide SS31 (H-DArg-Dmt-Lys-Phe-NH2) and the control peptide SS20 (H-Phe-D-Arg-PheLys-NH2), which lacks antioxidant properties, were synthesized in the laboratory of Dr. Peter W. Schiller, Clinical Research Institute of Montreal, using a published protocol (22).…”

Section: Reagentsmentioning

confidence: 99%

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Wang¹,

Malo

Hekimi³

2009

The Journal of Immunology

117

View full text Add to dashboard Cite

Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1α, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1+/− mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1+/− mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1α in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-α. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1α and secretion of TNF-α. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1α, which, in turn, is necessary for increased TNF-α secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1α activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1α expression can positively impact animal longevity.

show abstract

“…[Dmt] 1 -DALDA 3 is a highly potent MOR agonist that is able to cross the BBB and induce a potent analgesic effect in vivo. 21 When this sequence was conjugated to the NK1 fragments 4−6, the resulting hybrids 7−9 showed high affinity for the NK1 receptor, but disappointingly, their affinity and activity at μ-and δ-opioid receptors was drastically reduced. For this reason these compounds were not considered for further testing, and potential antagonism at the NK1 receptor was not determined.…”

mentioning

confidence: 99%

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

Betti

Starnowska

Mika

et al. 2015

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Herein, the synthesis and biological evaluation of dual opioid agonists−neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ-and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

show abstract

Synthesis and in vitro opioid activity profiles of DALDA analogues

Cited by 153 publications

References 16 publications

Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function

Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

Contact Info

Product

Resources

About