Why are there two prolines?

They come from the Pro-Gly-Pro extension, which was added to confer protease resistance. Proline constrains the backbone in a way most peptidases cannot accommodate.

Does Semax form disulfide bonds?

No. There is no cysteine in the sequence.

Why would a mass spectrum show +16 Da?

Oxidation of the single methionine to the sulfoxide. With one methionine, expect +16 rather than +32.

Semax (ACTH Fragment Peptide)

Semax Structure, Sequence and Physical Properties

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-232 cited sources

Semax has the sequence H-Met-Glu-His-Phe-Pro-Gly-Pro-OH: seven residues, molecular weight 813.9 Da, formula C37H51N9O10S. It contains two prolines that constrain backbone conformation, a single oxidation-prone methionine, and no cysteine, so no disulfide chemistry applies.

Key facts

Sequence: H-Met-Glu-His-Phe-Pro-Gly-Pro-OH
Residues: 7
Molecular weight: 813.9 Da
Molecular formula: C37H51N9O10S
Prolines: Two (positions 5 and 7)
Methionine: One (position 1) — oxidation-prone
Cysteines: None
Aromatic residues: Phe, His

Reading the sequence

In single-letter code the peptide is MEHFPGP: methionine, glutamate, histidine, phenylalanine, proline, glycine, proline. At 813.9 Da it is a genuinely small peptide — roughly a third the mass of MOTS-c and a fifth of semaglutide — which has consequences for both stability and analysis.

What the prolines do to the backbone

Proline is the only proteinogenic amino acid whose side chain closes back onto the backbone nitrogen. That ring removes the amide hydrogen and restricts rotation, so proline residues impose local conformational rigidity and interrupt regular secondary structure. Two prolines in a seven-residue peptide is a very high density, and the resulting constrained conformation is a large part of why Semax resists proteolysis.

Research material referenced

Semax 10mg — third-party HPLC tested

View — £24.99

Why proline-rich sequences resist peptidases

Most proteolytic enzymes need to bind an extended backbone conformation at their active site. Proline prevents the backbone adopting that geometry in its vicinity, so bonds adjacent to proline are poor substrates for the majority of peptidases. This is a general principle, not something specific to Semax, and it is why proline-rich motifs appear repeatedly in stabilised peptide design.

The histidine and the pH question

Histidine's imidazole side chain has a pKa near 6, meaning its charge state changes across the physiological range and across common buffer conditions. For a seven-residue peptide with a single histidine, that one residue carries a meaningful share of the molecule's pH-dependent behaviour, which is relevant when solubility or chromatographic retention shifts unexpectedly between buffers.

The methionine is the handling liability

Methionine at position 1 is the most chemically vulnerable feature. Its thioether sulfur oxidises readily to the sulfoxide in the presence of dissolved oxygen, accelerated by light and temperature, adding 16 Da. On a mass spectrum a degraded sample shows a +16 satellite alongside the parent mass. With only one methionine, +32 is not expected — unlike MOTS-c, which has two.

No disulfide chemistry

There is no cysteine in the sequence, so intramolecular or intermolecular disulfide formation is impossible and no reducing agent is required in buffers. Combined with the small size and proline rigidity, Semax is chemically among the more straightforward research peptides to handle — the methionine being the one thing to respect.

Quick reference

Property	Value
Sequence	MEHFPGP
Length	7 residues
Molecular weight	813.9 Da
Formula	C37H51N9O10S
CAS	80714-61-0
UNII	I5FAL2585H
PubChem CID	9811102

Extended research context

The Semax (ACTH Fragment Peptide) deep dive

Deep dive: what the Pro-Gly-Pro extension actually accomplishes

Semax is built from a four-residue fragment of ACTH with Pro-Gly-Pro appended, and that appendix does two separate jobs at once. Proline is the only proteinogenic amino acid whose side chain bonds back to its own backbone nitrogen, forming a ring that removes the amide hydrogen and locks rotation. Proteolytic enzymes generally need an extended, rotatable backbone at their active site, so bonds near proline are poor substrates for most of them — which is why proline-rich motifs recur throughout stabilised peptide design. The second job is subtractive: Pro-Gly-Pro occupies the positions where ACTH carries Arg-Trp-Gly, and those are the residues contributing to the parent hormone's adrenal-stimulating activity. One substitution therefore buys protease resistance and removes an unwanted pharmacology, which is unusually economical design.

Deep dive: the naming point worth getting right

Semax is near-universally described as an ACTH(4-10) analogue, and peer-reviewed paper titles use that phrase. Structurally it is not quite that. ACTH residues 4 to 10 are Met-Glu-His-Phe-Arg-Trp-Gly; Semax is Met-Glu-His-Phe-Pro-Gly-Pro. The first four residues match and the last three are wholly different — replacement rather than modification. PubChem, indexing by structure rather than design lineage, records it as ACTH(4-7) plus Pro-Gly-Pro. Neither name is wrong, but the loose one obscures the fact that the substituted segment is precisely the functionally consequential part.

Deep dive: reading an unevenly distributed evidence base

Semax's roughly 231 indexed records split along an unusual line. Mechanistic work — BDNF and trkB expression in rat hippocampus, transcriptomics in focal cerebral ischaemia, neurotrophin dynamics across brain regions — appears in international journals in English and can be assessed directly. Clinical work is concentrated in Russian-language publications, principally the Korsakov Journal of Neurology and Psychiatry, indexed by translated title and often without accessible English full text, much of it predating current standards for pre-registration and reporting. The honest position is that this is evidence which is difficult to verify independently, which is a different thing from evidence that is absent, and a different thing again from evidence that is established.

Research applications

▸Neurotrophin expression research (BDNF, NGF, TrkB, TrkA)
▸Neuroprotection and cerebral ischaemia models
▸Study of proline-stabilised peptide design
▸Comparative work on ACTH fragments without steroidogenic activity
▸Transcriptomic profiling in rodent brain models

Handling checklist

✓Store lyophilised material cold, dry and protected from light
✓Expect methionine oxidation as the degradation route (+16 Da; only one Met, so not +32)
✓No reducing agent needed — the sequence contains no cysteine
✓Introduce diluent gently against the vial wall; swirl rather than shake
✓Aliquot to avoid repeated freeze-thaw cycles
✓Check whether a certificate reports net peptide content or gross salt weight

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Describing Semax as ACTH(4-10) without qualification

Fix: It shares only residues 4-7; Pro-Gly-Pro replaces Arg-Trp-Gly, and that replacement is the design's whole point.

✗ Treating Russian registration as equivalent to MHRA approval

Fix: Authorisations are jurisdictional and do not transfer. Semax has never been assessed by the MHRA, EMA or FDA.

✗ Reading a BDNF expression change as a demonstrated outcome

Fix: The studies measured gene and protein expression in rats. Expression is upstream of function and upstream again of any clinical claim.

✗ Assuming a named receptor exists

Fix: No primary receptor has been definitively established; the literature characterises downstream effects more confidently than the initiating event.

✗ Expecting ACTH-like adrenal effects

Fix: Semax does not stimulate adrenal steroidogenesis — the responsible residues were substituted out.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Why are there two prolines?: They come from the Pro-Gly-Pro extension, which was added to confer protease resistance. Proline constrains the backbone in a way most peptidases cannot accommodate.
Does Semax form disulfide bonds?: No. There is no cysteine in the sequence.
Why would a mass spectrum show +16 Da?: Oxidation of the single methionine to the sulfoxide. With one methionine, expect +16 rather than +32.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

How we write and check this content Report a factual error in this article

More Semax (ACTH Fragment Peptide) articles

Popular across the research hub

One flagship guide from every other research category — keep exploring.

← Back to Forum