Semax: An ACTH(4-7) Plus Pro-Gly-Pro Peptide, Its Metal Chemistry and FDA Status

Semax is a short synthetic peptide with a long paper trail, and most of that trail is chemistry and rodent pharmacology rather than anything clinical. Its sequence joins a fragment of adrenocorticotropic hormone (ACTH) to a Pro-Gly-Pro tail. This Vial Post guide breaks down that design, looks at how the free N-terminus changes the way semax holds metal ions, lists what the animal studies measured, and summarizes FDA's compounding position.

The Vial Post covers semax strictly as a research subject. Nothing below is guidance on use in people or animals.

Quick Facts

• Sequence: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), PubChem CID 9811102 (PubChem: Semax).
• Formula and mass: C37H51N9O10S, 813.9 g/mol (PubChem: Semax).
• Synonym worth knowing: PubChem lists "ACTH (4-7), Pro-Gly-Pro-", which describes the design in one line (PubChem: Semax).
• Sulfur: the single S in the formula comes from the N-terminal methionine, which matters for metal binding (Magrì 2016).
• Regulatory note: FDA lists "Semax (heptapeptide)" among bulk drug substances nominated but withdrawn from category 2 (FDA bulk substances page).

Two Building Blocks

Researchers describe semax as encompassing the sequence 4-7 of ACTH's N-terminal domain plus a C-terminal Pro-Gly-Pro tripeptide (Tabbì 2015). Dolotov and colleagues call it an analogue of the ACTH(4-10) fragment (Dolotov 2006). The same Pro-Gly-Pro tail appears on selank, which instead starts with the tuftsin sequence; see our selank explainer.

Copper, Zinc and the N-Terminus

Two papers from Catania focus on semax as a metal-binding ligand:

• Copper affinity (2015). Equilibrium studies found three copper complex species. From pH 5, the [CuLH-2]2- species predominates, with the donor atoms around copper in a 4N planar arrangement. In SH-SY5Y neuroblastoma and RBE4 endothelial cell lines, copper-induced cytotoxicity was lower in the presence of semax in an MTT assay (Tabbì 2015).
• What acetylation changes (2016). Acetylating the N-terminal amine gives Ac-semax. Its main copper complex at physiological pH is a distorted CuN3O chromophore with a weak apical interaction from the methionine sulfur, unlike the CuN4 chromophore of copper-semax. Acetylation did not protect SH-SY5Y cells from copper-induced toxicity, which the authors read as showing the crucial role of the free NH2 terminus. Both peptides formed zinc complexes of comparable strength (Magrì 2016).

For a lab, the practical point is that "semax" and "N-acetyl semax" are different molecules with different metal chemistry, so the label and the measured mass need to agree.

What the Rodent Studies Measured

• Binding sites and BDNF (2006). Tritium-labelled semax bound rat basal forebrain membranes in a time-dependent, specific and reversible way that required calcium ions, with a KD of 2.4 nm and a BMAX of 33.5 fmol/mg protein. After intranasal application in rats, BDNF protein rose at 3 hours in the basal forebrain but not in the cerebellum (Dolotov 2006).
• Monoamine systems (2005). In rodents, striatal tissue 5-HIAA rose by 25% two hours after semax, and extracellular striatal 5-HIAA gradually increased up to 180% within 1 to 4 hours. Semax alone did not change dopamine or its metabolites, but given before D-amphetamine it enhanced that drug's effects on extracellular dopamine and locomotor activity (Eremin 2005).
• Serum enzymes (2001). Semax inhibited enkephalin-degrading enzymes in human serum with an IC50 of 10 microM (Kost 2001).

These results come from animal tissue and in vitro assays. They are not evidence of any effect in people, and The Vial Post does not report administered amounts.

FDA's Position

FDA's page on bulk substances that may present significant safety risks puts semax (heptapeptide) in the table of nominations withdrawn from category 2. It says compounded drugs containing semax may pose a risk of immunogenicity for certain routes of administration due to the potential for aggregation and peptide-related impurities. It adds that FDA has no, or limited, safety-related information for proposed routes of administration and so lacks sufficient information to know whether the drug would cause harm if administered to humans (FDA bulk substances page).

The broader policy context is in our interim compounding policy report.

Questions Readers Ask

Is semax the same as ACTH(4-10)? No. It keeps ACTH residues 4-7 and replaces the rest with Pro-Gly-Pro (Tabbì 2015; PubChem: Semax).

What is the molecular weight of semax? PubChem lists 813.9 g/mol (PubChem: Semax). Acetylated or salt forms will differ.

Does semax bind metals? Yes. It forms copper(II) and zinc(II) complexes, and N-terminal acetylation changes the copper complex geometry (Tabbì 2015; Magrì 2016).

Lab Note

Semax's only sulfur sits in its N-terminal methionine, and labels such as "N-acetyl semax" describe a different molecule. When reading a certificate, compare the reported mass with 813.9 g/mol and check that the purity method resolves related impurities. See our guide to HPLC versus mass spec.

For research and educational use only. This article is not medical advice and does not describe dosing or human use.