pe
pep-10790 v1 CC-BY-SA-4.0

Muscle-growth booster peptide (AR2mini): blocks the muscle-growth brake

A small experimental cyclic peptide that blocks myostatin's receptor, freeing the body's muscle-building potential; experimental, not yet an approved drug.

statusbioassayed targetACTIVIN-A length12 aa refs3
phage-displaycyclicdisulfideactriib-antagonist
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 5 / 5
key metrics
Kd ActRIIB 1.8 µM
IC50 Activin A 5 µM
sequence12 aa
151012
VCFGTSVRRICV
in the news 2 articles
Hypotheses6 directions▾ collapse

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.

openupdated 2026-06-05

Does the circular, locked shape of this peptide drive its ability to block the muscle-growth brake receptor, more than the specific amino acids it contains?

If true, scientists could redesign the ring geometry to make far more potent versions without needing to test every possible amino-acid combination. This could accelerate development of treatments for muscle-wasting diseases.

The hypothesis
The disulfide-constrained ring of AR2mini (C2-C11) presents the RR dipole and F3/I10 hydrophobic residues in a geometry that mimics the activin-A finger-2 loop contacting ActRIIB, making the cyclic scaffold the principal determinant of receptor affinity rather than any linear epitope.
Why it’s plausible
Phage-display selection on ActRIIB under disulfide-oxidizing conditions preferentially enriches constrained loop mimics. The two arginines (R8-R9) could engage the acidic D/E-rich ActRIIB ligand-binding domain, while F3 and I10 pack into a hydrophobic sub-pocket analogous to the activin-A knuckle epitope. A linearized (reduced) version would therefore lose most affinity, whereas the intact disulfide ring retains it.
Why it matters
Establishing the cyclic scaffold as the affinity driver would justify ring-size and stereochemical optimization rather than sequence mutagenesis alone, guiding second-generation antagonist design.
Plausibility.70
Novelty.60
Impact.70
Basis · grounding1 paper · 1 computed/note
[1]
sequenceCysteines at positions 2 and 11 define a 10-atom ring; RR at 8-9 and F3/I10 form two distinct pharmacophoric patches within the constrained loop.
[2]
paper
Phage-display identification of AR2mini as ActRIIB antagonist; cyclic/disulfide tag explicitly annotated, confirming oxidized ring is the selected form.
doi: 10.1016/j.bbrep.2017.06.001
openupdated 2026-06-05

Does this peptide selectively block only activin-A, while leaving the related myostatin signal intact at the same receptor?

Drugs that block both signals at once can cause side effects in the heart and reproductive system. A more selective peptide could boost muscle in disease with fewer unwanted effects, making it safer for long-term use in patients with muscular dystrophy or cancer cachexia.

The hypothesis
AR2mini preferentially antagonizes activin-A/ActRIIB over myostatin/ActRIIB signaling due to differential contacts in the ActRIIB ligand-binding domain, because activin-A and myostatin share the same receptor but bind overlapping, non-identical epitopes, and the phage display was performed with activin-A as bait.
Why it’s plausible
ActRIIB is the shared type-II receptor for multiple TGF-beta superfamily ligands including activin-A, myostatin (GDF-8), and GDF-11. Phage display against the receptor with activin-A as the competitive ligand would enrich peptides that block the activin-A footprint specifically. If myostatin contacts an adjacent but distinct sub-surface, AR2mini may spare myostatin signaling, producing a selectivity profile relevant to understanding its tissue-specific effects (activin drives gonadal and immune phenotypes; myostatin is more skeletal-muscle restricted).
Why it matters
Selectivity between activin-A and myostatin blockade matters clinically: full ActRIIB blockade (as seen with bimagrumab) causes reproductive and cardiovascular side effects partly attributed to broad ligand inhibition. A ligand-selective peptide antagonist would have a cleaner safety profile.
Plausibility.65
Novelty.55
Impact.80
Basis · grounding1 paper · 1 computed/note
[1]
paper
AR2mini selected by phage display on ActRIIB; selection ligand context (activin-A vs myostatin competition) determines footprint enriched.
doi: 10.1016/j.bbrep.2017.06.001
[2]
sequenceThe constrained 10-residue ring presents a limited surface that is more likely to fit one ligand-docking epitope than the full receptor binding surface shared by multiple ligands.
openupdated 2026-06-05

Could this peptide protect muscle mass in cancer patients by blocking a hormonal signal that tumors use to waste the body?

Cancer-related muscle loss kills patients faster and makes chemotherapy harder to tolerate. A peptide that blocks the wasting signal could help patients stay stronger and live longer, regardless of the cancer treatment they are receiving.

The hypothesis
AR2mini could attenuate cancer-associated muscle wasting (cachexia) driven by tumor-secreted activin-A in solid tumors, independently of any direct anti-tumor effect, because tumor INHBA overexpression elevates circulating activin-A that signals through skeletal muscle ActRIIB to suppress protein synthesis.
Why it’s plausible
Cachexia affects more than half of advanced cancer patients and directly reduces survival. Activin-A (INHBA homodimer) is a well-documented pro-cachectic ligand acting via ActRIIB on muscle. AR2mini was selected against ActRIIB and annotated as an activin-A antagonist, placing it mechanistically upstream of the muscle-wasting signal. Blocking this axis in the muscle compartment could preserve lean mass regardless of tumor burden.
Why it matters
No approved small-molecule ActRIIB antagonist exists for cachexia; a cyclic peptide scaffold is metabolically more tractable than a biologic antibody for this indication.
Plausibility.75
Novelty.40
Impact.80
Basis · grounding2 papers · 1 computed/note
[1]
paper
INHBA promotes tumor progression and its overexpression elevates activin-A, a known ActRIIB ligand implicated in systemic wasting.
doi: 10.1101/2023.12.07.570561
[2]
paper
AR2mini annotated as ActRIIB antagonist blocking activin-A signaling, directly relevant to muscle ActRIIB axis.
doi: 10.1016/j.bbrep.2017.06.001
[3]
sequence12-aa cyclic disulfide; small enough for synthetic optimization toward protease-resistant cachexia therapeutic.
openupdated 2026-06-05

Could adding a second internal bridge to this peptide stop the body from breaking it down too quickly?

Most peptide drugs are destroyed within minutes in the blood. A longer-lasting version of AR2mini could be injected once a day or less, making it a realistic drug candidate for patients with muscle-wasting conditions who need ongoing treatment.

The hypothesis
Bicyclization of AR2mini via a third anchor point on the G4 or T5 residue would rigidify the constrained loop further and increase proteolytic half-life in serum, because the current monocyclic disulfide still allows backbone breathing at the G4 hinge, and a second covalent tether would lock the pharmacophoric RR and hydrophobic residues into a single low-entropy binding-competent conformation.
Why it’s plausible
Glycine at position 4 introduces local backbone flexibility (no side chain, high phi/psi freedom) that is not constrained by the C2-C11 disulfide. Threonine at position 5 provides a hydroxyl handle for orthogonal conjugation chemistry (e.g., a thioether bridge via cysteine mimetic or a lactam to a K introduced at position 4). Bicyclic peptides derived by phage display (e.g., bicycle therapeutics platform) show dramatically improved serum stability and receptor affinity relative to monocyclic parents.
Why it matters
Serum half-life of unprotected disulfide peptides is typically minutes to low hours; a bicyclic version could reach subcutaneous dosing intervals compatible with clinical use for chronic conditions like cachexia or muscular dystrophy.
Plausibility.70
Novelty.50
Impact.70
Basis · grounding1 paper · 1 computed/note
[1]
sequenceG at position 4 is a known backbone flexibility hotspot; T at position 5 has an unreacted hydroxyl available for secondary crosslink chemistry.
[2]
paper
Cyclic/disulfide scaffold confirmed; current monocyclic form is the baseline from which further rigidification can be benchmarked.
doi: 10.1016/j.bbrep.2017.06.001
openupdated 2026-06-05

Could this muscle-focused peptide also help immune cells get into tumors that currently block them out?

Many cancers hide from the immune system by releasing signals that push immune cells away. If this peptide can cancel one of those signals, it could help immunotherapy drugs work in patients who currently do not respond to them.

The hypothesis
By antagonizing activin-A at ActRIIB, AR2mini could restore anti-tumor T cell infiltration in INHBA-overexpressing solid tumors, because activin-A suppresses CXCL9 and CXCL10 secretion by tumor cells, and blocking this axis could de-repress the chemokine gradient that recruits cytotoxic T cells.
Why it’s plausible
The literature snippet from DOI 10.1101/2023.12.07.570561 directly shows INHBA (activin-A precursor gene) promotes tumor growth by suppressing CXCL9/CXCL10, thereby excluding T cells. AR2mini blocks the activin-A/ActRIIB interaction. If the CXCL9/CXCL10 suppression is ActRIIB-mediated in tumor cells (which also express ActRIIB), then AR2mini could act as an immune de-exclusion agent, complementary to checkpoint inhibitors.
Why it matters
T cell exclusion is a major resistance mechanism for PD-1/PD-L1 blockade. A peptide that restores CXCL9/CXCL10 gradients could synergize with checkpoint therapy in cold tumors overexpressing INHBA.
Plausibility.55
Novelty.70
Impact.75
Basis · grounding2 papers
[1]
paper
INHBA promotes tumor growth by suppressing CXCL9/CXCL10 secretion from tumor cells, blocking T cell infiltration.
doi: 10.1101/2023.12.07.570561
[2]
paper
AR2mini is an ActRIIB antagonist, the receptor through which activin-A (INHBA product) signals.
doi: 10.1016/j.bbrep.2017.06.001
openupdated 2026-06-05

Are the two arginine building blocks in this peptide the critical contact points that allow it to block the muscle-growth brake?

Knowing exactly which part of a peptide grabs its target allows chemists to build smaller, cheaper, more stable versions that keep only the essential grip. This could translate into lower-cost drug candidates for patients with muscular dystrophy or severe muscle loss.

The hypothesis
The R8-R9 dipeptide within AR2mini constitutes a functionally essential electrostatic hot spot that engages a conserved acidic patch on the ActRIIB ligand-binding domain, and single alanine substitutions at either R8 or R9 would each individually abolish greater than 80% of binding affinity.
Why it’s plausible
The ActRIIB extracellular domain (ECD) contains a negatively charged surface that accommodates the basic finger-2 loop of activin-A. AR2mini, selected to compete with this interaction, presents two consecutive arginines (R8-R9) as the highest-charge-density feature in a 12-residue sequence. This dibasic motif is the most electrostatically prominent element in the ring and is positioned centrally in the constrained loop where it would be maximally exposed for receptor contact. Loss of either arginine would remove a full guanidinium group from a presumably tight ion-pair, predicting near-complete loss of function.
Why it matters
Identifying R8-R9 as the electrostatic anchor would define a minimal pharmacophore, enabling constrained peptidomimetic design (e.g., incorporation of non-natural diaminopropionic acid dimers) that retains charge while improving metabolic stability.
Plausibility.60
Novelty.50
Impact.65
Basis · grounding1 paper · 1 computed/note
[1]
sequenceR8 and R9 are the only basic residues in the 12-aa sequence; their central placement in the disulfide ring maximizes solvent exposure in a looped conformation.
[2]
paper
AR2mini was selected against ActRIIB, whose ligand-binding domain is known to present an acidic docking surface complementary to basic ligand loops.
doi: 10.1016/j.bbrep.2017.06.001
details expand to inspect
full evidence table6 metrics
metricvaluetool
Kd ActRIIB 1.8 µM SPR
Kd ActRIIA 19 µM SPR
IC50 Activin A 5 µM SMAD2/3 reporter assay (HEK293)
IC50 MSTN 6 µM SMAD2/3 reporter assay (HEK293)
IC50 GDF11 18 µM SMAD2/3 reporter assay (HEK293)
IC50 BMP9 12 µM SMAD2/3 reporter assay (HEK293)
3-letter notation
Val-Cys-Phe-Gly-Thr-Ser-Val-Arg-Arg-Ile-Cys-Val
citationbibtex
peptidemodel (2026). Muscle-growth booster peptide (AR2mini): blocks the muscle-growth brake (pep-10790, v1). PeptideModel. https://peptidemodel.com/card/pep-10790
@peptide{pep10790,
  sequence = {VCFGTSVRRICV},
  target   = {activin-a},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
clinical trials 0 trials · checked 2026-05-22
0
no registered clinical trials as of 2026-05-22; we'll re-check periodically
references 3 papers
discussion no comments
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