Somatostatin-14 growth-hormone brake (C14-modified research variant)
A lab-made version of a natural body signal that tells the pituitary gland to stop releasing growth hormone and quiets digestive juices; used only as a research tool.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Somatostatin-14 2 [C14 modified] is a synthetic cyclic analog of somatostatin-14, the natural 14-amino-acid hormone that instructs the pituitary to stop releasing growth hormone and suppresses secretion from the pancreas and gut. The stored sequence — AGCRNFFWKTFTSC — differs from native somatostatin-14 (AGCKNFFWKTFTSC) at a single position: arginine (R) replaces lysine (K) at position 4, making this the [Arg4] variant. The cyclic structure is formed by a disulfide bond between the two cysteines at positions 3 and 14 (Cys3–Cys14); that ring closure is not visible in the linear one-letter sequence shown here but is essential for receptor binding and biological activity. This variant is used as a laboratory research tool to probe somatostatin receptor pharmacology, and its Arg4 substitution has been studied specifically in the context of radiolabeled somatostatin analogs, where it is documented to preserve the biological activity of native SST-14 while reducing kidney retention (Tatsi and colleagues, EJNMMI Research 2012).
History
Somatostatin was discovered in 1972–1973 at the Salk Institute for Biological Studies by Paul Brazeau, Roger Guillemin, and colleagues, who were extracting sheep hypothalamic tissue in a search for a growth hormone-releasing factor. They found instead a peptide that potently inhibited growth hormone secretion from cultured pituitary cells — a result confirmed in human acromegalic patients with synthetic material. Guillemin chose the name "somatostatin" over the acronym SRIF (somatotropin-release-inhibiting factor); the paper appeared in Science on 5 January 1973. The 14-residue cyclic form (SST-14) is one of several bioactive fragments processed from a 116-amino-acid precursor. Because native SST-14 is degraded by plasma peptidases within roughly 1–3 minutes (Günther and colleagues, Pharmacological Reviews 2018), much of the field's work since the 1970s has focused on engineering more stable analogs; octreotide, introduced clinically in 1983, was the first to reach widespread use. The Arg4 modification present in this card emerged from efforts to improve renal handling of radiolabeled SST-14-based imaging agents, with multiple groups at the National Center for Scientific Research "Demokritos" in Athens and collaborating institutions in Switzerland and the Netherlands developing and characterizing this substitution (Tatsi and colleagues, EJNMMI Research 2012; Tatsi and colleagues, European Journal of Medicinal Chemistry 2014).
What it does
Like native somatostatin-14, this analog activates all five somatostatin receptor subtypes (SSTR1–5), a property described in the radiopharmaceutical literature as a "pansomatostatin" profile (Tatsi and colleagues, EJNMMI Research 2012). Activation of these receptors inhibits: growth hormone release from the anterior pituitary, insulin and glucagon secretion from pancreatic islets, and hormone release across gastrointestinal neuroendocrine cells. All five SSTR subtypes are inhibitory Gi-coupled class A GPCRs whose primary downstream effect is suppression of intracellular cAMP (Günther and colleagues, Pharmacological Reviews 2018). This broad SSTR coverage distinguishes native SST-14 — and analogs built on its 14-residue cyclic scaffold — from shorter clinical analogs like octreotide, which strongly prefer SSTR2. In the laboratory, the [Arg4] variant is used to probe somatostatin receptor binding-site interactions and to benchmark novel analogs against the natural hormone's broader receptor engagement.
Mechanism
The conserved Phe-Trp-Lys-Thr (FWKT) sequence at positions 7–10 of somatostatin-14 is the essential pharmacophore for SSTR recognition: it inserts into the orthosteric binding pocket of the receptor in a β-hairpin geometry that contacts transmembrane helices and extracellular loops (Li and colleagues, PNAS 2024; Günther and colleagues, Pharmacological Reviews 2018). The Cys3–Cys14 disulfide ring holds this pharmacophore in the correct conformation — experimental reduction of the disulfide causes a large loss of binding affinity and potency in SST-14-based analogs. Within the receptor, Gi-coupling suppresses adenylyl cyclase and reduces cAMP, opens inward-rectifier potassium channels (GIRK), and curtails voltage-operated calcium currents, collectively inhibiting hormone secretion and, in some tissues, cell proliferation (Günther and colleagues, Pharmacological Reviews 2018). Position 4 — where this analog carries arginine in place of the native lysine — lies outside the FWKT pharmacophore and tolerates substitution: both residues carry a positive charge, and the arginine variant retains the full somatostatin receptor activity of the parent peptide (Tatsi and colleagues, EJNMMI Research 2012).
Evidence
- Human: No clinical trials have been conducted or registered for this specific [Arg4]-modified analog. Native somatostatin-14 was confirmed in human acromegalic patients to lower plasma growth hormone at its initial characterization (Brazeau and colleagues, Science 1973); that work used native SST-14, not this variant.
- Animal: Radiolabeled derivatives of DOTA-coupled SST-14 analogs built on the same 12-member cyclic ring (Cys3–Cys14 framework) have been evaluated in rodent tumor xenograft models expressing individual SSTR subtypes, with receptor-specific uptake confirmed by competitive blockade (Tatsi and colleagues, EJNMMI Research 2012). A related ring-size reduction study in mice showed that the 12-residue and 9-residue ring variants achieved sstr2-specific tumor uptake, while shorter analogs lost SSTR affinity (Tatsi and colleagues, European Journal of Medicinal Chemistry 2014).
- In vitro: Cyclic SST-14-based analogs retaining the full 12-member Cys3–Cys14 ring display nanomolar IC₅₀ values across all five human SSTR subtypes in competitive radioligand binding assays, with agonist activity confirmed by receptor internalization at SSTR2 and SSTR3 (Tatsi and colleagues, EJNMMI Research 2012). Structural studies confirm the FWKT motif as the essential contact with all five receptor subtypes (Li and colleagues, PNAS 2024).
Known effects
- Growth hormone inhibition — Core activity of the SST-14 scaffold; the Arg4 substitution preserves this by maintaining the FWKT pharmacophore and the Cys3–Cys14 cyclic architecture. No direct data for this specific variant; supported by analog class data.
- Pansomatostatin SSTR1–5 engagement — Mechanistic; supported by in vitro binding data for closely related 12-member ring analogs and structural data (Tatsi and colleagues, EJNMMI Research 2012; Li and colleagues, PNAS 2024). Distinguishes native SST-14 analogs from SSTR2-selective clinical tools.
- Reduced kidney retention vs. Lys4 analogs — Rationale for the Arg4 substitution documented in the radiolabeled-peptide literature (Tatsi and colleagues, EJNMMI Research 2012).
Safety signals
No formal safety data have been published for this specific [Arg4]-modified analog. Native somatostatin-14 has an established pharmacological profile from decades of short-term clinical and research use; its half-life of roughly 1–3 minutes limits systemic accumulation. The [Arg4] modification is a conservative charge-preserving substitution and is not expected to introduce new toxicophores, but no toxicology studies for this specific variant were identified in the available literature.
Regulatory status
- US: Not approved. Research reagent only; no registered clinical program.
- EU: Not approved. Research reagent only.
- ClinicalTrials.gov: No registered trials identified for this [Arg4]-modified somatostatin-14 analog.
- WADA: Somatostatin and its analogs are listed under the Prohibited List (S2, Peptide Hormones, Growth Factors, Related Substances and Mimetics) because of their growth hormone-inhibitory action; this class prohibition applies to the somatostatin scaffold.
Open questions
- The precise chemical identity of the "C14 modified" designation in the card name warrants clarification — whether it refers solely to the cysteine-14 position forming the disulfide ring (standard for all SST-14 cyclic analogs) or to an additional chemical modification at Cys14 (such as conjugation or isotopic labeling) is not established in the available literature.
- Direct receptor binding assays (IC₅₀ at SSTR1–5) for this free, unconjugated [Arg4]-SST-14 have not been reported separately from the DOTA-chelated derivatives.
- No crystal or cryo-EM structure of [Arg4]-SST-14 in complex with any SSTR subtype has been solved.
Related peptides
- Octreotide (/card/pep-04436) — The first clinically approved somatostatin analog (1983); an 8-residue cyclic peptide with strong SSTR2 preference and metabolic stability. Unlike this 14-residue pansomatostatin analog, octreotide lacks coverage of SSTR1, SSTR3, and SSTR4 at clinically relevant concentrations.
- Somatostatin-14 (native, AGCKNFFWKTFTSC) — The parent compound; differs from this card's analog only at position 4 (Lys vs. Arg) and carries the same Cys3–Cys14 disulfide ring.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
If this variant sticks less to kidney tissue while still homing in on tumors, could doctors use higher doses for clearer scans or stronger cancer treatment?
Patients with neuroendocrine tumors could receive more effective radiation therapy or sharper diagnostic images with less risk of kidney damage, which is currently a major limiting factor.
If swapping one amino acid changes which receptor this peptide hits hardest, could it suppress growth hormone without as many metabolic side effects?
People with acromegaly or children with gigantism might get a treatment that controls excess growth hormone more precisely, with fewer problems from blood sugar swings or digestive side effects.
If changing one charged amino acid locks the peptide into a shape that fits its target more snugly, could that explain why it works differently from the natural hormone?
Scientists could use this insight to deliberately design peptides with locked shapes, making drugs that are more potent and longer-lasting than natural hormones.
If the computer model correctly captured the ring-shaped structure that nature uses, could we trust it to design better versions of this hormone?
Drug designers could use computer models to rapidly test thousands of ring-shaped peptide variants, speeding up the search for better treatments without as much lab work.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9469568729400635 | boltz-2 |
| ranking score | 0.8589351773262024 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.572 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10490,
sequence = {AGCRNFFWKTFTSC},
target = {ghsr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}