AC-SDKP (TB-500 Fragment)

Mechanism of action

AC-SDKP (N-acetyl-Ser-Asp-Lys-Pro) is a constitutively released tetrapeptide generated from the N-terminus of thymosin beta-4 through sequential cleavage by prolyl oligopeptidase. Its primary catabolic route is hydrolysis at the Pro–Gly bond by angiotensin-converting enzyme (ACE, somatic form). This biochemical relationship is clinically relevant: ACE inhibitors, by blocking AC-SDKP degradation, raise endogenous plasma AC-SDKP concentrations by approximately four- to five-fold in humans, a phenomenon documented by Rousseau and colleagues (Am J Hypertension, 1995). This rise in endogenous AC-SDKP is one proposed mechanism underpinning the anti-fibrotic benefits of ACE-inhibitor therapy in cardiovascular and renal disease, beyond the peptide's haemodynamic effects. At the cellular level, AC-SDKP inhibits the proliferation of haematopoietic progenitor cells in the G1/S phase transition, keeping a proportion of multipotent stem cells in quiescence — a role that originally attracted pharmaceutical interest in the context of cytoprotection during myelosuppressive chemotherapy. The anti-fibrotic effects that have drawn more recent research attention are mediated primarily through suppression of TGF-β1/Smad-2/3 signalling in cardiac and renal fibroblasts. Animal data show that AC-SDKP reduces nuclear translocation of phospho-Smad-3, decreases fibronectin and collagen-I synthesis, and attenuates the differentiation of fibroblasts into myofibroblasts (alpha-smooth muscle actin-positive cells). It also inhibits macrophage-to-myofibroblast transition in the renal interstitium. Separately, in endothelial cell cultures, AC-SDKP promotes tube formation and migration in a manner that is dependent on VEGFR2 activation, suggesting a pro-angiogenic secondary profile that may support tissue repair following ischaemic injury. In the pulmonary context, AC-SDKP has been reported to reduce bleomycin-induced interstitial fibrosis, collagen deposition, and myofibroblast accumulation, expanding the potential tissue-scope of its anti-fibrotic action beyond the heart and kidney.

ACE inhibition raises endogenous plasma AC-SDKP four- to five-fold, providing mechanistic evidence that part of the anti-fibrotic benefit of ACEi drugs in cardiac and renal disease is mediated through AC-SDKP accumulation rather than angiotensin-II suppression alone (Rousseau et al., Am J Hypertension, 1995).

— Notable finding

Research history

AC-SDKP was first characterised as a haematopoietic regulatory factor in the late 1980s by Lenfant and colleagues in France, who noted that this small N-acetylated tetrapeptide, purified from bone-marrow extracts, selectively inhibited pluripotent stem-cell entry into the S phase of the cell cycle. Its name reflects its amino-acid sequence: Ac-Ser-Asp-Lys-Pro. Early work focused on its potential as a cytoprotective agent during cytotoxic chemotherapy, shielding haematopoietic progenitors from proliferation-dependent myelosuppression. The biochemical link to thymosin beta-4 (Tβ4) as the endogenous precursor was established in the mid-1990s, and the identification of prolyl oligopeptidase as the generating enzyme and ACE as the degrading enzyme gave AC-SDKP a clear position within the renin-angiotensin-aldosterone system regulatory network. Rousseau's group in Paris was central to defining the pharmacokinetic interaction with ACE inhibitors. From approximately 2005 onwards, the centre of gravity in AC-SDKP research shifted towards fibrosis. Rodrigo Loiola Ramos, Marcos Ferraz, and particularly the group of Oscar Carretero at the Henry Ford Hospital in Detroit published a series of studies demonstrating potent anti-fibrotic activity in cardiac, renal, and pulmonary models. The peptide has sometimes been referred to informally as Goralatide in the context of therapeutic development proposals. Interest in combining AC-SDKP with ACE-inhibitor therapy as a mechanistic synergy — rather than the peptide alone — has informed discussion of dosing strategy in pre-clinical fibrosis research. The commercial availability of synthetic AC-SDKP as a research compound has grown considerably since 2015, partly because of cross-over interest from those researching thymosin beta-4 and its marketed fragment TB-500. However, AC-SDKP is structurally, pharmacologically, and mechanistically distinct from the central actin-binding region of Tβ4 that constitutes most 'TB-500' commercial peptide preparations.

Reported research-model dose ranges

The ranges below are taken from published pre-clinical literature. They do not constitute a dosing recommendation for human use.

Summarised studies

Safety profile

AC-SDKP is an endogenous peptide circulating in human plasma at concentrations in the low nanomolar range. Its endogenous status is generally regarded as favouring a high baseline safety profile, and acute toxicology studies in rodents have not identified dose-limiting adverse effects at concentrations substantially above those achievable by ACE-inhibitor-mediated elevation. The principal theoretical concern in a research context is the haematopoietic suppressive activity: at concentrations well above physiological, AC-SDKP inhibits pluripotent stem-cell proliferation, and sustained supraphysiological exposure could theoretically impair regenerative haematopoiesis. In practice, this concern has not translated into observed cytopenias in any published animal study using therapeutic-range dosing. Because AC-SDKP is a tetrapeptide of 487 Da, immunogenicity in humans is considered negligible — it is well below the threshold at which peptides typically elicit antibody responses, and its endogenous nature means immune tolerance is expected. Sterility and endotoxin content of research-grade preparations remain the dominant practical safety variables, as with all injectable research peptides. Batch-to-batch verification by HPLC and mass spectrometry, and endotoxin testing by limulus amebocyte lysate (LAL) assay, are standard due-diligence expectations. Long-term human systemic dosing data do not exist outside of the indirect exposure provided by ACE-inhibitor therapy. The effects of bolus exogenous AC-SDKP on reproductive endpoints, oncogenic risk, or immune competence in humans remain entirely unstudied.

UK regulatory status

AC-SDKP (Goralatide) is not authorised as a medicinal product by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and has not received a marketing authorisation in any jurisdiction as of the current date. It is not a controlled substance under the Misuse of Drugs Act 1971 or the Misuse of Drugs Regulations 2001. AC-SDKP is not explicitly named on the World Anti-Doping Agency (WADA) Prohibited List; however, WADA's S0 category ('Non-Approved Substances') covers any pharmacological substance not approved by any regulatory authority for human therapeutic use, which would encompass AC-SDKP administered for performance or recovery purposes in competitive sport. Researchers should consult the current annual WADA Prohibited List for the definitive position. Possession of AC-SDKP for bona fide in-vitro or ex-vivo laboratory research purposes is unrestricted in the United Kingdom. Supply for human administration, or administration to a third party, would likely engage medicines-regulation provisions and should not be undertaken outside of an authorised clinical trial framework. No UK enforcement actions concerning AC-SDKP supply specifically are known to this publication.

Frequently asked questions