Semax

Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro, constructed from the ACTH(4-7) fragment of adrenocorticotropic hormone extended at the C-terminus with the tripeptide Pro-Gly-Pro, supplied as a research chemical and not approved by the FDA for any use.

The naming is a frequent source of confusion. Semax is described in the literature both as an "ACTH(4-10) analogue" and as "ACTH(4-7)PGP", and both descriptions are correct. Residues 4 through 10 of the 39-residue ACTH sequence are Met-Glu-His-Phe-Arg-Trp-Gly. Semax retains the first four of those residues and replaces Arg-Trp-Gly with Pro-Gly-Pro. It is therefore an analogue of the 4-10 fragment that contains only the 4-7 core of the parent hormone. Semax is not ACTH and does not contain the full hormone sequence.

Specifications

Design rationale and research origin

Semax was developed by Russian investigators in the 1980s within a broader programme on short ACTH-derived peptides. The design problem the Pro-Gly-Pro extension addresses is proteolytic lability: short linear peptides are rapidly cleaved in plasma, and the C-terminal proline-containing tail was intended to slow that degradation. Potaman et al. (1991), in Biochemical and Biophysical Research Communications, characterised the degradation of ACTH(4-10) and of Semax by rat blood enzymes, reporting that cleavage proceeds from the N-terminus. Subsequent work by the same group extended that analysis to rat serum enzyme inhibitors. The practical consequence reported across this literature is a short circulating lifetime in the rodent models studied, which is why so much of that work is designed around rapid clearance.

Binding and molecular targets

Dolotov et al. (2006), in Journal of Neurochemistry, reported specific, time-dependent and reversible binding of tritium-labelled Semax to plasma membranes of the rat basal forebrain, with a dissociation constant of 2.4 ± 1.0 nM and a B_max of 33.5 ± 7.9 fmol/mg protein. That is evidence of a saturable high-affinity site in rat tissue; it does not identify the molecular entity involved. Despite the melanocortin lineage of the parent sequence, no receptor has been definitively assigned to Semax in the published literature, and its relationship to the melanocortin receptor family remains unresolved.

A separate chemical property is metal coordination. Tabbì et al. (2015), in the Journal of Inorganic Biochemistry, reported that Semax binds copper(II) with high affinity, forming several complex species across a pH range, and measured copper-induced cytotoxicity in vitro in neuroblastoma and endothelial cell lines. Those are coordination-chemistry and cell-culture observations and describe no outcome in an organism. The histidine imidazole and the free N-terminal amine make the copper affinity chemically unsurprising, and it is relevant to laboratory practice: trace metal content in buffers and glassware can alter the species actually present in a Semax solution.

Neurotrophin-related findings in rodent models

The most-cited mechanistic thread concerns brain-derived neurotrophic factor. Shadrina et al. (2001), in Neuroscience Letters, reported rapid induction of neurotrophin mRNAs in rat basal forebrain glial cell cultures following Semax exposure in vitro. Dolotov et al. (2006), in Brain Research, reported that a single application in rats produced an approximately 1.4-fold increase in hippocampal BDNF protein and an approximately 1.6-fold increase in trkB tyrosine phosphorylation, alongside roughly 3-fold and 2-fold increases in exon III BDNF and trkB mRNA respectively.

Two points of interpretation belong with those numbers. The protein-level changes are modest in magnitude, considerably smaller than the transcript-level changes, and were measured in rat brain tissue. Fold-change in a neurotrophin transcript is a molecular observation and is not itself a behavioural or clinical outcome.

Monoamine and transcriptome studies

Eremin et al. (2005), in Neurochemical Research, examined effects on dopaminergic and serotonergic systems in rodents using neurochemical measurement of monoamines and their metabolites.

Ischemia models account for much of the modern literature. Medvedeva et al. (2014), in BMC Genomics, performed genome-wide transcriptional analysis in a rat focal cerebral ischemia model and reported that a majority of the genes whose expression was altered by Semax fell within immune-response categories, with an additional group associated with vascular formation and function. Filippenkov et al. (2020), in Genes, extended transcriptome-level analysis to cerebral ischaemia-reperfusion in rats. Both are descriptive expression studies in rodents: they characterise which gene sets move, not whether a therapeutic effect exists in humans.

State of the human evidence

Semax has been registered as a medicine in the Russian Federation since the 1990s, and a Russian-language clinical literature exists in which it was studied in stroke and cognitive indications. Much of that literature consists of small studies whose randomisation, blinding, allocation concealment and trial registration are not documented to contemporary reporting standards. It has not been replicated in adequately powered, independently conducted trials indexed in the international literature. Registration as a medicine in one jurisdiction is not evidence of efficacy under FDA standards and is not FDA approval. For any indication in the United States, there is no established human efficacy evidence.

Analytical identity and documentation

The methionine residue at position 1 makes Semax more analytically demanding than a peptide of comparable length without a sulfur-containing residue. Methionine oxidises readily to the sulfoxide, producing a +16 Da species that is straightforward to see by LC-MS but easy to miss on a purity number alone. A documentation package worth trusting will include reversed-phase HPLC purity with the chromatogram attached, mass confirmation against 813.9 g/mol for the free base with any oxidised species identified rather than integrated silently, the counter-ion and its content, water content by Karl Fischer, residual solvent data, and, where relevant, endotoxin and trace metal testing. Reading and comparing these documents across suppliers is covered under lab testing.

N-acetyl Semax and N-acetyl Semax amidate are distinct chemical entities with their own CAS numbers, masses, and stability profiles. They are not Semax, and a COA for one does not characterise the other.

Handling and storage

The lyophilised solid is stored at −20 °C, desiccated, and protected from light and air. Because of the methionine residue, exposure to air, oxidants, and elevated temperature is the principal chemical risk to lot integrity, and it produces a change that will not necessarily be visible. Solutions are markedly less stable than the solid and are additionally sensitive to trace metals in buffers and glassware. Repeated freeze-thaw cycling of stock solutions is a common and avoidable source of inter-experiment variability. General laboratory handling practice is collected under peptide storage and reconstitution, and stock concentration arithmetic can be worked through with the peptide calculator.

Regulatory status

Semax is not approved by the FDA for any indication in the United States and is not a dietary ingredient. Its registration status in the Russian Federation confers no United States regulatory standing. The classification of research peptides under United States compounding law has been actively changing, and current status should be verified against primary FDA sources rather than secondary or commercial summaries. Material supplied here is for laboratory research use only and is not for human or animal consumption. See the research use policy.

FAQ

Why is Semax called both an ACTH(4-10) analogue and ACTH(4-7)PGP?

Both names describe the same molecule. Semax retains ACTH residues 4-7 (Met-Glu-His-Phe) and substitutes Pro-Gly-Pro for residues 8-10 (Arg-Trp-Gly). It is an analogue of the 4-10 fragment built on the 4-7 core.

What storage conditions apply?

Lyophilised solid at −20 °C, desiccated, protected from light and air. The N-terminal methionine is oxidation-sensitive, so air exposure and warm storage are the main degradation risks. Solutions are less stable than the solid and are sensitive to trace metal contamination.

Is Semax approved by the FDA?

No. Semax is not FDA approved for any indication in the United States and is not a dietary ingredient. It has been registered as a medicine in Russia since the 1990s, which is a separate regulatory system and does not constitute FDA approval or evidence meeting FDA evidentiary standards.

Is N-acetyl Semax the same compound?

No. N-acetyl Semax and N-acetyl Semax amidate are separate chemical entities with different CAS numbers, molecular weights, and stability characteristics. Documentation should identify which specific compound was synthesised and assayed.