Treatment of mitochondria with antioxidants SS-19 and SS-31

Stuart

Stuart

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3rd Annual Community Symposium on the Molecular Basis of ME/CFS at Stanford University, sponsored by OMF, 7th Sept 2019
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Hillary Johnson‏ @oslersweb 9h9 hours ago


Ron Davis: SS-19, an experimental drug that repairs mitochondria, designed for people with congestive heart failure, turned ME blood into control blood. OMF working with inventor.


http://novelconjugates.com/product/tyrosol-ss19carbamate/

Tyrosol-SS19(Carbamate)
novelconjugates June 12, 2018 No Comments

$800.00

Quantity: 25mg

SKU: 3204004 Category: Peptide conjugates Tag: Tyrosol-Szeto-Schiller peptide
Description
Product Name: Tyrosol-SS19(Carbamate)

Synonyms: Tyrosol-Tyr-D-Arg-Phe-Lys-NH2,

Cat#: 3204004

M.F.: C39H53N9O8

M.W.: 775.91

Description: In addition to its antioxidative effects, tyrosol has the neuroprotective, anti-inflammatory, antiaging, and antifungal properties. SS19 is one of the small, cell-permeable antioxidant peptides (Szeto-Schiller or SS peptides) that are known to protect mitochondria from oxidative damage.


http://novelconjugates.com/product/resveratrol-ss19carbamate/

Resveratrol-SS19(Carbamate)
novelconjugates June 12, 2018 No Comments

$800.00

Quantity: 25mg

SKU: 3204003 Category: Peptide conjugates Tags: Resveratrol-SS19, Resveratrol-Szeto-Schiller peptide
Description
Product Name: Resveratrol-SS19(Carbamate)

Synonyms: Resveratrol-Tyr-D-Arg-Phe-Lys-NH2,

Cat#: 3204003

M.F.: C45H55N9O9

M.W.: 865.99

Description: Resveratrol (3,5,4′-trihydroxy-trans-stilbene), a natural phytoalexin found in grape-skin, exerts multiple biological activities, including anti-inflammatory, antiproliferative and antioxidant effects. SS19 is one of the small, cell-permeable antioxidant peptides (Szeto-Schiller or SS peptides) that are known to protect mitochondria from oxidative damage.


http://novelconjugates.com/product/ss31/

Szeto-Schiller peptide(SS31）
novelconjugates June 12, 2018 No Comments

$1,500.00

Quantity: 25mg

SKU: 3902004 Category: Peptides Tags: SS31, Szeto-Schiller (SS) peptides
Description
Product name: SS31

Synonym: Elamipretide, Bendavia, H-D-Arg-Tyr(2,6-diMe)-Lys-Phe-NH2, H-D-Arg-Dmt-Lys-Phe-NH2,

IUPAC Name: (2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide,

Catalog #: 3902004

CAS No.: 736992-21-5

Molecular Formula: C32H49N9O5

Molecular Weight: 639.80

Description: SS31 is a tetra-peptide, cell-permeable, mitochondria-targeted molecule. The SS31 is one of the four molecules (SS31, SS02, SS19, SS20) developed by Szeto and Schiller that is capable of targeting and permeating to mitochondria. The chemical structure of SS31 is H-D-Arg-Dmt-Lys-Phe-NH2, and its structural motif centers on alternating aromatic residues and basic amino acids. SS31 has a sequence motif that allows it to target mitochondria, scavenge free radicals, including H2O2 and ONOO−, and inhibit lipid peroxidation. Its capability of protecting to be attributed to tyrosine, or dimethyltyrosine, a residue that scavenges oxyradicals and forms relatively unreactive tyrosyl radicals. The unreactive tyrosyl radicals trigger the coupling of tyrosyl radicals to each other, giving rise to dityrosine, which reacts with a superoxide to form tyrosine hydroperoxide. Recently, the efficacy of SS31 was studied in rodent models of ischemic brain injury, diabetes, myocardial infarction and amyotrophic lateral sclerosis (ALS). These researchers found that SS31 protects cells from mitochondrial toxicity in all of these disease states. SS-31 represents a novel platform of mitochondria-targeted antioxidants with broad therapeutic potential.
 
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Open Access
2011, 8(1), 203-221; https://doi.org/10.3390/ijerph8010203

Article
Toxicity of Neurons Treated with Herbicides and Neuroprotection by Mitochondria-Targeted Antioxidant SS31
by Tejaswini P. Reddy 1, Maria Manczak 1, Marcus J. Calkins 1, Peizhong Mao 1, Arubala P. Reddy 1, Ulziibat Shirendeb 1, Byung Park 2 and P. Hemachandra Reddy 1,3,*
1
Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
2
Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
3
Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
*
Author to whom correspondence should be addressed.
Received: 31 December 2010; in revised form: 13 January 2011 / Accepted: 17 January 2011 / Published: 19 January 2011
Abstract
:
The purpose of this study was to determine the neurotoxicity of two commonly used herbicides: picloram and triclopyr and the neuroprotective effects of the mitochondria-targeted antioxidant, SS31.

Using mouse neuroblastoma (N2a) cells and primary neurons from C57BL/6 mice, we investigated the toxicity of these herbicides, and protective effects of SS1 peptide against picloram and triclopyr toxicity. We measured total RNA content, cell viability and mRNA expression of peroxiredoxins, neuroprotective genes, mitochondrial-encoded electron transport chain (ETC) genes in N2a cells treated with herbicides and SS31.

Using primary neurons from C57BL/6 mice, neuronal survival was studied in neurons treated with herbicides, in neurons pretreated with SS31 plus treated with herbicides, neurons treated with SS31 alone, and untreated neurons. Significantly decreased total RNA content, and cell viability in N2a cells treated with picloram and triclopyr were found compared to untreated N2a cells.

Decreased mRNA expression of neuroprotective genes, and ETC genes in cells treated with herbicides was found compared to untreated cells. Decreased mRNA expression of peroxiredoxins 1–6 in N2a cells treated with picloram was found, suggesting that picloram affects the antioxidant enzymes in N2a cells.

Immunofluorescence analysis of primary neurons revealed that decreased neuronal branching and degenerating neurons in neurons treated with picloram and triclopyr. However, neurons pretreated with SS31 prevented degenerative process caused by herbicides. Based on these results, we propose that herbicides—picloram and triclopyr appear to damage neurons, and the SS31 peptide appears to protect neurons from herbicide toxicity.

Keywords:
Mitochondria-targeted antioxidant; herbicides; Picloram; Triclopyr; Szeto-Schiller peptide 31; mouse neuroblastoma cells; mouse primary hippocampal neurons; electron transport chain; oxidative stress


" We purchased the SS31 peptide, a mitochondria-targeted antioxidant, from AnaSpec, CA. The SS31 tetra-peptide was originally synthesized by Dr. Hazel H. Szeto in collaboration with Dr. Peter W. Schiller. Drs. Szeto and Schiller designed and synthesized four different peptides (SS31, SS02, SS20, and SS19) with the amino acids Dmt, D-Arg, Phe, and Lys, and with the Dmt residue [27]. The peptide SS31 was chosen for our study because it targets mitochondria and penetrates into cells and the mitochondria several hundred times [27]. When the SS31 peptide penetrates into mitochondria, tyrosine (Tyr) and dimethyltyrosine (Dmt) analogs from the peptides scavenge and diminish free radicals, such as H2O2, OH, and ONOO [27–29]. SS31 also prevents lipid peroxidation [27–29]. At low molar concentrations (e.g., 1 nM), SS31 is reported to protect mammalian cells, including neurons, from mitochondrial and other toxic insults [30]. Therefore, we used a 1 nM final concentration of SS31 in this study. "

https://www.mdpi.com/1660-4601/8/1/203/htm

PDF
https://www.researchgate.net/publication/49833123_Toxicity_of_Neurons_Treated_with_Herbicides_and_Neuroprotection_by_Mitochondria-Targeted_Antioxidant_SS31
 
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Volume 1762, Issue 2, February 2006, Pages 256-265

Review
Targeting antioxidants to mitochondria: A new therapeutic direction
Author links open overlay panelShey-ShingSheuaDhananjayaNauduribM.W.Andersa
https://doi.org/10.1016/j.bbadis.2005.10.007Get rights and content
Under an Elsevier user license
open archive
Abstract
Mitochondria play an important role in controlling the life and death of a cell. Consequently, mitochondrial dysfunction leads to a range of human diseases such as ischemia–reperfusion injury, sepsis, and diabetes. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not fully elucidated yet, the oxidative stress appears to be critical. Accordingly, strategies are being developed for the targeted delivery of antioxidants to mitochondria. In this review, we shall briefly discuss cellular reactive oxygen species metabolism and its role in pathophysiology; the currently existing antioxidants and possible reasons why they are not effective in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially targeted antioxidants and their future promise for disease treatment.

Keywords
Reactive oxygen species
Antioxidant
Mitochondria
Mitochondria membrane potential
Oxidative stress
1. Introduction
There is a continuing search for better and more effective antioxidants. The recent recognition of mitochondria as an arbiter of the life and death of cells has drawn awareness to the need to develop antioxidants and other cytoprotective agents targeted to mitochondria. Physiologically, mitochondria perform a variety of key cellular regulatory processes, including ATP production, intracellular Ca2+ regulation, reactive oxygen species (ROS) generation and detoxication, and apoptosis [1]. Mitochondria use approximately 90% of the consumed O2 for oxidative phosphorylation and ATP synthesis. Thus, the proteins involved in the mitochondrial electron transport chain are probable sites for ROS generation. Intracellular glutathione, glutathione peroxidase, glutathione transferases, catalase, superoxide dismutase, and a variety of other antioxidant defenses keep ROS concentrations in check, which allows cells to function homeostatically and to prevent oxidative stress [2], [3], [4], [5], [6]. A shift in the balance between ROS generation and destruction to overproduction or decreased detoxication is associated with chronic diseases [7].

During the last 5 years, research effort in developing mitochondria-targeted antioxidants has increased steadily. This is exemplified by recent studies showing that triphenylphosphonium-based antioxidants and amino acid- and peptide-based antioxidants protect mitochondria against oxidative insult. One can envision that the future efforts in exploiting the unique biophysical and biochemical properties of mitochondria for the targeted delivery of cytoprotective agents will increase rapidly.

______________________________________________________________

5.2. Amino acid- and peptide-based, mitochondrially targeted antioxidants
5.2.1. SS tetrapeptides (Fig. 4)
The SS tetrapeptides are aromatic–cationic peptides that bear the structural motif of alternating aromatic and basic amino acid residues along with a 2′,6′-dimethyltyrosine (Dmt) residue [52]. The antioxidant properties of these tetrapeptides apparently stem from the presence of Dmt; the related compound 3,5-dimethylphenol is a known phenolic antioxidant [53]. The SS tetrapeptides were originally prepared in an attempt to develop centrally acting opioid analgesics [54], [55], [56]. The compounds studied included Dmt–D-Arg–Phe–Lys–NH2 (SS-02), Phe–D-Arg–Phe–Lys–NH2 (SS-20) (a tetrapeptide that lacks the antioxidant Dmt), and D-Arg–Dmt–Lys–Phe–NH2 (SS-31); Dmt–D-Arg–Phe–atnDap–NH2 (SS-19), a fluorescent analog in which β-anthraniloyl-l-α,β-diaminoproprionic acid replaces Lys4, was prepared to study mitochondrial and cellular uptake.

1-s2.0-S0925443905001535-gr4.jpg

  1. Download full-size image
Fig. 4. Structures of antioxidant SS tetrapeptides. SS-02, Dmt–D-Arg–Phe–Lys–NH2; SS-20, Phe–D–Arg–Phe–Lys–NH2; SS-31, D-Arg–Dmt–Lys–Phe–NH2; Dmt, 2′,6′-dimethyltyrosine.

SS-02 scavenges H2O2 and inhibits the oxidation of linoleic acid and low-density lipoproteins (LDL), thereby demonstrating the antioxidant properties of these tetrapeptides [52]. SS-31, which contains the same amino acid residues as SS-02 but in a different sequence, shows antioxidant properties similar to SS-02, but the analog SS-20, which lacks the Dmt residue, did not demonstrate antioxidant activity. SS-02 is taken up by Caco-2 cells; the intracellular concentration is approximately 10-times the extracellular concentration. Confocal imaging studies of Caco-2 cells show that intracellular distribution of SS-19 resembles that of MitoTracker TMRM, which localizes in mitochondria. The uptake of [3H]SS-02 and SS-19 by isolated mouse liver mitochondria is rapid, and the mitochondrial accumulation amounts to approximately 105-fold. Incubation of mitochondria with FCCP reduces the uptake of [3H]SS-02 and SS-19 by approximately 20%, indicating a partial potential-dependent uptake. Digitonin treatment of the mitochondria showed that about 85% of [3H]SS-02 was present in the mitoplast (inner mitochondrial membrane and matrix).

A panel of in vitro experiments showed that SS-31 and SS-02 protect neuronal N2A cells from tert-butylhydroperoxide-induced ROS generation and cytotoxicity, Caco-2 cells against 3-nitropropionic acid-induced mitochondrial depolarization, and isolated mitochondria from hydrogen peroxide-induced ROS generation and calcium-induced swelling and mitochondrial permeability transition (MPT); SS-20 lacks antioxidant properties in these experiments. Finally, SS-02 and SS-31 protect against the loss of contractile force induced by 30 min of global ischemia in the isolated perfused guinea pig heart, whereas SS-20 failed to prevent the loss of contractile function associated with reperfusion. These studies show that these cell-permeable tetrapeptides are effective antioxidants in a range of in vitro studies. Moreover, these small peptides do not require the attachment of a cationic molecule to be accumulated preferentially in mitochondria. Thus they may have the advantage in exerting effective antioxidant action in depolarized mitochondria.

https://www.sciencedirect.com/science/article/pii/S0925443905001535

Interesting article, long, and on many antioxidants. PDF is available to download.
 
SS-31 Is a Novel Mitochondrial-Targeted Therapy That Crosses Blood-Brain Barrier

Drs. Felsen and Poppas are researching a highly promising mitochondrial-targeted drug candidate, known as SS-31, which targets the inner mitochondrial membrane (IMM). As Dr. Felsen explained, its discovery was completely serendipitous.

"It was designed for something totally different," she said. "Discovering that SS-31 went into the IMM has led to a new first-in-class group of compounds that can restore cellular bioenergetics."

SS-31 belongs to the Szeto-Schiller (SS) family of peptides. Dr. Felsen's colleague, Hazel H. Szeto, MD, PhD, was researching the ability of one of these peptides, SS-02, to bind to the mu-opioid receptor and accidentally discovered its potential for crossing the blood-brain barrier. Subsequent studies showed that SS-02 could readily cross cell membranes and target the IMM (J Biol Chem 2004;279:34682-34690). Eventually, the peptide analog SS-31 was designed to selectively target the IMM, while having a negligible effect on opioid receptors.

https://urology.weillcornell.org/dr...-targeted-therapy-crosses-blood-brain-barrier
 
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Here is something about Mitochondria-penetrating peptides (MPPs) for cancer therapy.

Mitochondrial-targeted Penetrating Peptide Delivery for Cancer Therapy
Article in Expert Opinion on Drug Delivery 15(10) · September 2018 with 49 Reads
DOI: 10.1080/17425247.2018.1517750
Cite this publication

Jiao Wu
Jason Li
Hu Wang

Chang-Bai Liu
28.83China Three Gorges University

Abstract
Introduction: Mitochondria play a key role in activation of programmed cell death and are promising targeting organelles for anti-cancer strategies, However, Mitochondria are difficult for antineoplastic drugs to recognize and bind.

Mitochondria-penetrating peptides (MPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into Mitochondria. As a delivery vector, MPPs has combined or delivered a variety of anti-tumor cargoes and obviously inhibited the tumor growth in vivo and in vitro.

MPPs creating new opportunities to develop new treatments for cancer. Areas covered: This review describes the target sites of mitochondria and the target-penetration mechanism of MPPs.

We also review different strategies that have been used on recent publications, various additional strategies decorated MPPs have been used to achieve tumor cell mitochondria targeting, the decorating mattes including metabolism molecules, RNA, DNA and protein, which exploited considered as therapeutic combine with MPPs and target in human cancer treatment.

Expert Opinion/Commentary: Despite recent advances in the field, much work is needed to deepen, such as the therapeutic selectivity that preferentially target the mitochondrial abnormalities in cancer cells without toxic impact on normal cells.

Moreover, it needs appropriate study designs for a correct evaluation of the target delivery outcome and the degradation rate of the drug in the cell.

Generally, it is optimistic that the advances in mitochondrial targeting drug delivery by MPPs plasticity outlined here will ultimately help to the discovery of new approaches for the prevention and treatment of cancers.

https://www.researchgate.net/public...netrating_Peptide_Delivery_for_Cancer_Therapy
 
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