ArticleeLife2022
Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- An FGF21-based fusion protein ameliorates mitochondrial dysfunction and promotes recovery post spinal cord injury.Materials today. Bio · 2026Article
- Elamipretide Rejuvenates Oocyte Quality and Restores Female Fertility During Reproductive Aging.Aging cell · 2026Article
- Strategic Targeting of Mitochondria: Bridging Biology and Therapy for Health Benefits.Cell biochemistry and biophysics · 2026Review
- Next-Generation Antioxidants in Cardiovascular Disease: Mechanistic Insights and Emerging Therapeutic Strategies.Antioxidants (Basel, Switzerland) · 2026Review
- Mitochondria-Targeted Peptides and Bilayer Composition Modulate Membrane Electroporation under Elevated Electrochemical Stress.Langmuir : the ACS journal of surfaces and colloids · 2025Article
- Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.Acta neuropathologica communications · 2025Review
- Targeting High-Density Aromatic Peptides to Cardiolipin Optimizes the Mitochondrial Membrane Potential and Inhibits Oxidative Stress.FASEB bioAdvances · 2025Article
- Contemporary insights into elamipretide's mitochondrial mechanism of action and therapeutic effects.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- Article
- Mitochondrial dysfunction and apoptotic signaling induced by the combined action of 2-aminoethyl dihydrogen phosphate and methyl-β-cyclodextrin in melanoma cells.Frontiers in pharmacology · 2025Article
- Mitochondria-Targeted Nanosystems in the Treatment of Central Nervous System Diseases.International journal of nanomedicine · 2025Review
- The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age.bioRxiv : the preprint server for biology · 2024Article
- Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.Protein science : a publication of the Protein Society · 2024Article
- Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.bioRxiv : the preprint server for biology · 2024Article
- Interactions and Transport of a Bioconjugated Peptide Targeting the Mitomembrane.Bioconjugate chemistry · 2024Article
- Cardiovascular aging: spotlight on mitochondria.American journal of physiology. Heart and circulatory physiology · 2024Review
- Peptide Power: Mechanistic Insights into the Effect of Mitochondria-Targeted Tetrapeptides on Membrane Electrostatics from Molecular Simulations.Molecular pharmaceutics · 2023Article
- Mechanisms of Modulation of Mitochondrial Architecture.Biomolecules · 2023Review
- Development and Characterization of Innovative Multidrug Nanoformulation for Cardiac Therapy.Materials (Basel, Switzerland) · 2023Article
- Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.Frontiers in physiology · 2023Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.