TB-500

Molecular identity

Formula

C212H350N56O78S

Molecular weight

4963 g/mol

CAS

77591-33-4

PubChem CID

16132341

What it acts on

• Monomeric G-actin — the reviews describe a complex with the actin monomer whose dissociation constant is in the micromolar range, an affinity low enough for fast binding and release, so the peptide buffers the unpolymerised monomer pool rather than locking it away; it is unstructured in solution and folds into a stable conformation only on binding.
• Actin polymerisation (G-actin to F-actin) — reported to inhibit filament formation by controlling monomer availability, which together with nucleating, severing and uncapping proteins is how the literature frames the cellular polymerisation response.
• The SRF–MRTF–G-actin transcriptional axis — the cardioprotection review attributes the large number of pleiotropic effects to the peptide's many interactions with cellular signalling pathways, and singles out indirect regulation of cell motility and movement through this axis.
• Ac-SDKP, a degradation fragment — several of the effects catalogued in the reviews are ascribed not to the intact peptide but to Ac-SDKP possibly generated from it, or to oxidised thymosin β4, and antifibrotic activity is reported for the degradation products as well as the parent.
• Inflammatory and redox gene programmes — the sepsis review summarises reported reductions in inflammatory mediators and reactive oxygen species alongside up-regulation of anti-oxidative enzymes, anti-inflammatory genes and anti-apoptotic enzymes.

What the studies report

Each item below summarises the paper it is numbered to, written from that paper's own abstract. The badge says how the evidence was produced.

1. 1.
   reviewAnn N Y Acad Sci (2007)

   A historical and mechanistic review of the β-thymosins. It traces thymosin β4 from its isolation out of thymosin fraction 5, where it was sought as a thymic hormone — the authors state that none of the isolated peptides really were thymic hormones — to the 1990 demonstration by Safer and colleagues that it sequesters G-actin, with a dissociation constant in the micromolar range that permits fast binding and release. It reports that β-thymosins are the main intracellular G-actin-sequestering peptides in most vertebrate cells, that the peptide is unstructured until it folds onto actin, and that it is found in the nucleus as well as the cytoplasm. It notes that several biological effects are attributed to thymosin β4, to oxidised thymosin β4, or to Ac-SDKP possibly generated from thymosin β4, and it names its own gap plainly: very little is known about the molecular mechanisms mediating the effects attributed to extracellular β-thymosins.

2. 2.
   reviewAnn N Y Acad Sci (2007)

   A review of actin dynamics in non-muscle cells, where the availability of monomers and of nucleating sites sets the polymerisation response. It reports that overexpression or addition of exogenous thymosin β4, or of its homolog thymosin β10, alters the actin cytoskeleton and has multiple effects on motility-related cell functions. Its central point is a discrepancy the authors do not resolve: some of those effects are consistent with a protein acting purely as a monomer binder and others are not, so they propose a mixture of direct and indirect effects on the cytoskeleton plus modulation of signalling pathways. Titled "the β-thymosin enigma", it documents an unsettled mechanism rather than closing it.

3. 3.
   reviewExpert Opin Biol Ther (2018)

   A review of actin regulation in sepsis, assembled from a literature search rather than from new experiments. It reports that thymosin β4 inhibits polymerisation of G-actin into F-actin and that administration improved mortality in septic rats, and it summarises decreased inflammatory mediators, lowered reactive oxygen species and up-regulated anti-oxidative enzymes, anti-inflammatory genes and anti-apoptotic enzymes. It also notes that sepsis is accompanied by measurable circulating F-actin and reduced thymosin β4 concentrations. The authors mark their own reasoning as speculative — F-actinaemia is "speculated" to disturb laminar flow in the microcirculation — and their conclusion is that the question should be pursued in a human clinical trial, which is to say no such trial is reported here.

4. 4.
   reviewVitam Horm (2016)

   A review chapter on cardioprotection, covering preclinical models of cardiac ischaemic injury in which thymosin β4 is reported to reduce infarct volume and preserve cardiac function. The authors attribute those effects in part to decreased infarct size, with additional benefits described as likely due to specific antifibrotic and proangiogenic activities; they note increased blood-vessel growth in both small and large animal models and in transgenic animals, and report that the peptide and its degradation products have antifibrotic effects in vitro and in animal fibrosis models unrelated to cardiac injury. They ascribe the large number of pleiotropic effects to the peptide's many interactions with cellular signalling pathways, particularly indirect regulation of cell motility and movement through the SRF–MRTF–G-actin transcriptional pathway. They also record the weaknesses: effect sizes vary between animal models, potentially because distribution of the protein varies, and they state that preclinical PK/PD studies and a reliable pharmacodynamic biomarker would be needed to facilitate clinical development.

Used in research on