Cell-grip blocker related to Cilengitide (cycloRGDFC)
A small ring-shaped peptide that interferes with the molecular handles cells use to grip their surroundings, an approach being explored to slow tumor growth; experimental, not an approved drug.
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
cycloRGDFC is a designed five-residue cyclic peptide built around the RGD motif — the short Arg-Gly-Asp sequence that many proteins in the body use to grab onto cells through receptors called integrins (Ruoslahti 1996). It is described here as an analog of Cilengitide, the first small-molecule cyclic-RGD drug candidate, which reached late-stage cancer trials as an integrin inhibitor (Mas-Moruno 2010). The stored sequence "RGDFC" is the bare backbone — the active form is cyclized (most commonly head-to-tail or through a disulfide/thioether involving the C-terminal Cys), and the phenylalanine at position 4 is the D-isomer, mirroring the c(RGDfV) design pattern that gave Cilengitide its potency.
History
The RGD tripeptide was identified by Erkki Ruoslahti's group in the 1980s as the minimal cell-attachment site shared across fibronectin, vitronectin, fibrinogen and many other adhesive proteins; roughly half of the 20+ known integrins recognize this sequence (Ruoslahti 1996). Linear RGD peptides bind integrins only weakly and non-selectively. To fix that, Kessler and colleagues developed "spatial screening" in the early 1990s, cycling and rigidifying RGD-containing pentapeptides to lock the side-chains into the geometry preferred by a single integrin subtype. The resulting c(RGDfV) — a cyclic pentapeptide with a D-phenylalanine at position 4 — was the first superactive αvβ3 inhibitor, reported to be 100- to 1000-fold more potent than linear RGD peptides and highly selective against the platelet integrin αIIbβ3. Cilengitide is the N-methylated derivative c(RGDf(NMe)V) and entered clinical phase III for glioblastoma and phase II for several other tumors (Mas-Moruno 2010). cycloRGDFC sits in this same chemical lineage: a cyclic RGD pentapeptide with D-Phe at position 4, but with cysteine in place of valine.
What it does
In the body, integrins on the surface of cells (especially endothelial cells lining new blood vessels, and cells migrating into a wound) latch onto matrix proteins by recognizing exposed RGD sequences. A cyclic RGD peptide drug acts as a decoy ligand: it occupies the integrin's RGD-binding pocket without delivering the structural cues a real matrix protein would, blocking cell adhesion, migration and angiogenic signaling through αvβ3 and related αv-class integrins (Mas-Moruno 2010, Ruoslahti 1996). The Cys at position 5 of cycloRGDFC provides a free thiol that is commonly used as a handle for further conjugation — for example, attaching the peptide to a larger scaffold, a fluorophore, or a surface — while preserving the RGD binding face.
Mechanism
The αvβ3, αvβ5 and α5β1 integrins are the principal RGD-recognizing receptors targeted by Cilengitide and its close analogs (Mas-Moruno 2010). Cyclization plus the D-amino acid at position 4 forces the RGD side-chains into a kinked turn conformation that fits the αvβ3 binding cleft and disfavors binding to αIIbβ3, the bleeding-risk platelet integrin. Subsequent work on macrocyclic RGD ligands — for example, head-to-side-chain cyclic peptides assembled by sortase A-mediated ligation — has continued to refine this scaffold for both potency and selectivity at αvβ3 (Wu 2017).
The raw five-letter sequence stored on this card (RGDFC) does not, on its own, capture two features that matter biologically: the macrocyclic backbone (the peptide is closed into a ring, typically using the Cys side chain or head-to-tail amide closure) and the D-stereochemistry at position 4 (the F is D-Phe, not L-Phe). Without those, this would be a weak linear peptide rather than a high-affinity integrin ligand.
Evidence
- Human: No human studies of cycloRGDFC itself are present in the dossier. The parent compound Cilengitide (c(RGDf(NMe)V)) reached phase III in glioblastoma and phase II in several other tumor types as of the Mas-Moruno 2010 review.
- Animal: No animal studies of this specific analog are present in the dossier.
- In vitro: The cyclic RGD pentapeptide scaffold from which cycloRGDFC is derived was reported as a 100- to 1000-fold more potent αvβ3 inhibitor than linear RGD references, with high selectivity over αIIbβ3 (Mas-Moruno 2010). Macrocyclic RGD peptides built on related backbones retain potent and selective αvβ3 binding (Wu 2017).
Known effects
- αv-integrin binding (αvβ3, αvβ5, α5β1) — Established for the parent c(RGDfV) / Cilengitide scaffold (Mas-Moruno 2010). This specific analog has not been independently characterized in the dossier.
- Anti-angiogenic activity — Mechanism-level only, inferred from the parent compound; not measured for this exact peptide in the dossier.
- Conjugation handle (Cys thiol) — Structural feature of this analog; biological consequences are application-dependent.
Open questions
- Binding affinity (IC50 / Ki) of cycloRGDFC at αvβ3, αvβ5 and α5β1 vs. the reference c(RGDfV) — not reported in the dossier.
- Cyclization chemistry assumed in this card (disulfide via Cys5? thioether? head-to-tail amide with Cys retained as a free-thiol pendant?) — the platform sequence does not disambiguate; primary characterization is needed.
- Whether the Phe→Cys substitution at position 5 (relative to Cilengitide's Val) preserves αvβ3 selectivity over αIIbβ3, or shifts the integrin-subtype profile.
- Relevance of an αv-integrin ligand to the card's declared "tissue-repair" target — RGD/integrin biology is involved in cell adhesion during wound healing, but no specific tissue-repair data for this peptide is in the dossier.
Related peptides
- The parent scaffold c(RGDfV) and the clinical compound Cilengitide (c(RGDf(NMe)V)) — the historical templates this analog is built from (Mas-Moruno 2010).
- Other macrocyclic RGD peptides developed as αvβ3 ligands (Wu 2017).
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.
Can this peptide selectively dial down the signaling that causes excess scar tissue, while leaving the process that closes the wound surface intact?
A treatment that reduces scarring without slowing wound closure would be valuable for burns, surgical patients, and people prone to keloids, where current options force a tradeoff between healing speed and scar quality.
Does the unique ring shape of cycloRGDFC make it home in on the integrin found on tumor vessels while leaving the platelet integrin largely alone?
If true, the peptide could block tumor blood-vessel growth without raising the bleeding risk that troubled earlier RGD drugs, making it a safer candidate for cancer therapy.
Can the unique sulfur atom in cycloRGDFC be used to anchor it onto drug-carrying nanoparticles, and does loading more of the peptide per particle make them home in on tumors more effectively?
If this works, it would give oncologists a way to deliver chemotherapy directly to tumor blood vessels while sparing healthy tissue, potentially reducing the devastating side effects of systemic chemotherapy.
Does the cysteine in cycloRGDFC form a short-lived chemical link with wound-site proteins, making the peptide act longer than a simple non-sticky drug would?
If so, lower doses might achieve the same tissue-repair benefit, reducing cost and potential side effects, which matters for patients with chronic wounds or surgical repair needs.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| ranking score | 0.6190606951713562 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | none_monomer |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-23 |
▸citationbibtex
@peptide{pep10783,
sequence = {RGDFC},
target = {tissue-repair},
author = {peptidemodel},
year = {2026},
status = {computed}
}