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1kits（10Vials）
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▎SS-31 Structure
Source: PubChem | Sequence: RXKF Molecular Formula: C32H49N9O5 Molecular Weight: 639.8g/mol CAS Number: 736992-21-5 PubChem CID: 11764719 Synonyms: Elamipretide |
▎SS-31 Research
What is the research background of SS-31?
The research background of SS-31 stems from an in-depth understanding of mitochondrial dysfunction and the limitations of existing therapeutic approaches. Mitochondria are pivotal for cellular activity and function, and their dysfunction is associated with the onset and progression of various diseases, such as kidney disease, neurodegenerative disorders, and heart failure. In these conditions, abnormalities in mitochondrial biogenesis, morphology, function, and dynamic changes emerge, making mitochondria a critical therapeutic target. Although several mitochondrial-targeted drugs exist—including NAD+ supplements like nicotinamide mononucleotide (NMN), the mitochondrial-targeted protective compound MitoQ, and the antioxidant coenzyme Q10—traditional medications face clinical limitations due to poor mitochondrial uptake or high toxicity. Consequently, there is a pressing need to develop more effective, targeted therapies.
Stress-induced heart failure represents one of the primary causes of heart failure globally, with its pathophysiology closely linked to mitochondrial dysfunction and myocardial interstitial fibrosis. Identifying effective therapeutic approaches is crucial for improving patient outcomes. Against this backdrop, researchers developed SS-31, a novel mitochondrial-targeted antioxidant, to address the therapeutic needs for mitochondrial dysfunction-related diseases. It specifically acts on the inner mitochondrial membrane, stabilizing mitochondrial structure and function while reducing oxidative stress, demonstrating efficacy in multiple disease models.
What is the mechanism of action of SS-31?
Regulating mitochondrial membrane function
Interaction with cardiolipin: Elamipretide crosses the outer mitochondrial membrane and binds to cardiolipin. Cardiolipin is a key phospholipid component of the inner mitochondrial membrane, playing a crucial role in maintaining mitochondrial structure and function. Through this interaction, Elamipretide improves mitochondrial bioenergetics and morphology. This process manifests as rapid enhancement of mitochondrial function in induced pluripotent stem cells, particularly in cells derived from patients with Barth syndrome and other inherited pediatric cardiomyopathies[1].
Altering membrane physical properties: Mitchell W's research indicates that Elamipretide interacts with the lipid bilayer, modifying the physical properties of the mitochondrial membrane, particularly the electrostatic properties at the membrane interface. This peptide distributes to the membrane interface region with affinity and binding density directly correlated to surface charge. While it does not destabilize the lamellar bilayer at high binding concentrations, it induces saturation changes in lipid stacking, thereby affecting mitochondrial membrane function[2].
Figure 1 Factors affecting cardiac energy supply and demand[1].
Protecting the Nervous System
Enhancing Cognitive Function: In a lipopolysaccharide (LPS)-induced mouse model of memory impairment, Elamipretide treatment significantly improved learning and memory abilities in the Morris water maze (MWM) and conditioned place fear tests. This ameliorative effect may be associated with its protection of mitochondrial function, reduction of oxidative stress, regulation of the brain-derived neurotrophic factor (BDNF) signaling pathway, and enhancement of synaptic structural complexity. LPS treatment induced mitochondrial dysfunction, oxidative stress, inflammation, neuronal apoptosis, and dendritic spine loss in the mouse hippocampus, while Elamipretide mitigated these injuries, demonstrating potential in preventing perioperative neurocognitive dysfunction (PND)[3].
Inhibition of Neuronal Apoptosis: In spinal cord injury (SCI) studies, Elamipretide promotes functional recovery by suppressing pyroptosis, enhancing autophagy, and reducing lysosomal membrane permeability (LMP). It enhances autophagy by inhibiting cPLA2 phosphorylation while mitigating pyroptosis and LMP. Thus, Elamipretide plays a crucial role in repairing neurological injuries by regulating multiple cellular processes, reducing neuronal apoptosis, and promoting neural functional recovery[4].
Figure 2 Elamipretide (SS-31) attenuated oxidative stress and the inflammatory response induced by LPS in the mouse hippocampus. a Reactive oxygen species (ROS) levels, b malondialdehyde (MDA) levels, and c superoxide dismutase (SOD) activities[3].
What are the applications of SS-31?
Neurological Disorders
Treatment of Traumatic Optic Neuropathy: Traumatic optic neuropathy (TON) can cause permanent vision loss due to blunt orbital trauma. Studies have investigated the neuroprotective effects of SS-31 combined with the tumor necrosis factor (TNF) inhibitor etanercept on retinal ganglion cells (RGCs) following optic nerve injury. Tse B C's study using a mouse ultrasound-induced TON model (SI-TON) found that intravitreal injection of SS-31 combined with subcutaneous injection of etanercept and SS-31 significantly increased RGC survival by 21% (p < 0.01) compared to phosphate-buffered saline (PBS)-treated control eyes. Combined subcutaneous injection of etanercept and SS-31 increased RGC survival by 11% (p < 0.05) compared to controls; subcutaneous injection of etanercept alone increased RGC survival by 20% (p < 0.01) compared to controls; Subcutaneous injection of SS-31 alone increased RGC survival by 17% compared to the control group (p < 0.01). These findings indicate that SS-31 exerts a protective effect on RGCs in treating traumatic optic neuropathy, thereby improving visual acuity in TON patients [5].
Improvement in α-Synuclein-Related Neurodegenerative Diseases: Parkinson's disease and related synucleinopathies are closely associated with the membrane binding and aggregation properties of α-synuclein. Stefaniak's research confirms that SS-31 can dose-dependently displace both wild-type and N-terminal acetylated α-synuclein from negatively charged small monolayer vesicles, inhibit membrane-induced α-synuclein aggregation, and alter its fibrillar morphology. Furthermore, SS-31 restores the displacement of synuclein from negatively charged small monolayer vesicles, inhibits membrane-induced α-synuclein aggregation, and alters its fibrillar morphology. Additionally, SS-31 can restore the displacement of synuclein - from negatively charged small unilamellar vesicles, inhibit membrane-induced α-SNIP aggregation, and alter its fibrillar morphology. Furthermore, SS-31 restored impaired mitochondrial function in neuroblastoma cells treated with α-SNIP oligomers and blocked cellular uptake of these oligomers. These findings highlight SS-31's multifaceted protective effects against α-synuclein aggregation-induced mitochondrial dysfunction, positioning it to mitigate neurodegenerative diseases associated with α-synuclein misfolding and aggregation[6].
Cardiovascular Disease Domain
Improving Mitochondrial Function in Heart Failure Patients: Adverse mitochondrial alterations are known to exist in heart failure (HF) patients. Studies treated fresh ex vivo failing and non-failing ventricular tissue from children and adults with SS-31, measuring mitochondrial oxygen flux, complex (C)I and CIV activity, and gel-based activity of supercomplex assembly. Chatfield's findings demonstrate impaired mitochondrial function in failing human hearts. Following SS-31 treatment, mitochondrial oxygen flux, CI and CIV activity, and CIV activity related to supercomplex assembly significantly improved, indicating SS-31 effectively enhances mitochondrial function in failing human hearts and can intervene in heart failure[7].
Treatment of Barth Syndrome Cardiomyopathy: Barth syndrome is a rare and potentially fatal X-linked disorder characterized by high infant mortality and progression to cardiomyopathy with severe immune system impairment. SS-31 is a water-soluble, aromatic cationic, mitochondrial-targeted tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane. It promotes cellular health and alleviates oxidative stress by enhancing energy production and suppressing excessive reactive oxygen species formation. Sabbah research demonstrates that SS-31 rapidly improves mitochondrial bioenergetics and morphology in induced pluripotent stem cells derived from patients with Barth syndrome. Data from multiple disease models indicate SS-31 holds promise as a potential therapy for patients with Barth syndrome cardiomyopathy, demonstrating particularly pronounced effects in those diagnosed with cardiomyopathy. It may exert a lasting impact on cardiomyopathy progression while progressively structurally reversing the remodeling of failing left ventricles at global, cellular, and molecular levels[1] .
Musculoskeletal Disease Domain: Demonstrated therapeutic potential in tendinopathy. Zhang X's study utilized a mouse supraspinatus tendinopathy model, dividing 126 mice (252 limbs) into six experimental groups. Results from Zhang X indicate that tendon rupture force decreased post-impact compared to intact tendons. This reduction was partially reversed after clamp removal, SS-31 treatment, or combined therapy, with stiffness exhibiting a similar pattern. Histological analysis revealed higher modified Bonar scores in the impact group, while combined therapy partially reversed morphological changes in the tendon. The impacted group exhibited reduced mitochondrial numbers and altered cristae organization and density. Following clamp removal and/or SS-31 treatment, mitochondrial structure and quantity normalized, and cristae morphology improved. Superoxide dismutase (SOD) activity decreased post-impact compared to controls but increased significantly after treatment, particularly in the combined therapy group. Mitochondria-related gene expression decreased in the impact group but rebounded after treatment. This demonstrates that SS-31, as a mitochondrial protector, improves mitochondrial function and promotes tendon healing, with enhanced efficacy when combined with subacromial impingement removal. It holds positive therapeutic potential for supraspinatus tendinopathy [8].
Conclusion
SS-31 (Elamipretide), as a mitochondrial-targeted tetrapeptide, achieves mitochondrial function protection and multi-system injury repair. It binds to phosphatidylserine in the inner mitochondrial membrane, stabilizing membrane structure and potential, enhancing respiratory chain complex activity to promote ATP production, and improving cellular energy metabolism. Simultaneously, it suppresses excessive reactive oxygen species (ROS) generation, upregulates antioxidant enzyme activity, and mitigates oxidative stress damage. Regarding inflammatory regulation, it inhibits NF-κB and NLRP3 inflammasome activation, reducing pro-inflammatory factor release. It modulates autophagy pathways, suppresses apoptosis, and maintains mitochondrial homeostasis through related pathways. These actions confer beneficial effects in diseases involving mitochondrial dysfunction across cardiovascular, neurological, and musculoskeletal systems.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Kathryn C. Chatfield is a researcher at the University of Colorado School of Medicine, affiliated with the Departments of Pediatrics and Medicine/Division of Cardiology. She focuses on pediatric cardiology and mitochondrial biology, investigating the mechanisms underlying heart function and disease. She has contributed extensively to the field through scholarly publications and collaborations, and her work is recognized for advancing understanding of cardiovascular physiology and potential therapeutic strategies. Kathryn C. Chatfield is listed in the reference of citation [7].
