Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds.

Mitchell W, Tamucci JD, Ng EL, Liu S, Birk AV, Szeto HH, May ER, Alexandrescu AT, Alder NN

eLife1 Aug 2022Cited by 24 (Europe PMC)

PMID35913044PMCIDPMC9342957DOI10.7554/elife.75531PepBankPUB-35913044

Summary

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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

2 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Activity measurement
In mammalian cell culture, the tetrapeptides including SS‑31 permeated cells and targeted mitochondria.
In plain wordsIn cultured cells, SS‑31 and the three analogs entered cells and reached mitochondria.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableCell permeation and mitochondrial targeting
Study
n: not reported in source
Mammalian cell culture
Outcome group
Mitochondrial function · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3591304402
02LabIn vitro (cells)Activity measurement
In serum withdrawal cell stress models, SS‑31 and the three analogs were pharmacologically active, with significant differences in restoring mitochondrial membrane potential, preserving ATP and promoting cell survival.
In plain wordsIn stressed cultured cells, SS‑31 and three analogs were all active, but differed in how well they restored mitochondria and cell survival.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableActivity in serum withdrawal stress models (membrane potential, ATP, survival)
Study
n: not reported in source
Serum withdrawal cell stress models
Outcome group
Mitochondrial function · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3591304403

Studies that did not test the peptide alone1

In this study, Elamipretide (SS-31) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Elamipretide (SS-31).

03LabNot a test of Elamipretide (SS-31) aloneIn vitro (cell-free)Mechanism
In NMR and molecular dynamics models of the membrane-bound state, SS‑31 did not form the compact reverse turn that the three analogs formed.
In plain wordsIn lab structure models, SS‑31 did not fold into the compact turn shape that the three tested analogs formed.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableMembrane-bound reverse turn conformation
Study
n: not reported in source
NMR and molecular dynamics structural models, membrane-bound state
Outcome group
Receptor activity and mechanism · Pharmacology
Source sentences
Summary
showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
In this study, Elamipretide (SS-31) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Elamipretide (SS-31).
Show in the study text Report a problemFND-3591304401

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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