Ac-SDKP

The acetylated N-terminal tetrapeptide of thymosin beta-4, degraded almost exclusively by ACE and studied in animals as an antifibrotic and anti-inflammatory signal, with the only human studies of the administered peptide run in the 1990s as a chemotherapy myeloprotectant.

Also referenced as: Goralatide, Seraspenide, AcSDKP, Ac-Ser-Asp-Lys-Pro, N-acetyl-Ser-Asp-Lys-Pro, N-acetyl-seryl-aspartyl-lysyl-proline, Acetyl-N-Ser-Asp-Lys-Pro, Thymosin Beta-4 Fragment (1-4)

Also appears in: Tissue repair

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What is Ac-SDKP?

Ac-SDKP is N-acetyl-Ser-Asp-Lys-Pro, a four-residue peptide of about 487 daltons (C20H33N5O9; CAS 120081-14-3) that occurs naturally in human plasma, urine, and tissue at low nanomolar concentrations — measured baselines in healthy volunteers sit around 1.7 to 3.2 nM. It is the acetylated N-terminal tetrapeptide of thymosin beta-4 — literally residues 1 through 4 of the 43-amino-acid parent protein — and it was first isolated from fetal calf bone marrow as an inhibitor of hematopoietic stem cell proliferation (Lenfant et al., Proceedings of the National Academy of Sciences, 1989;86(3):779–782). Its International Nonproprietary Name is goralatide; the same molecule was developed under the name seraspenide.

Two separate literatures drive interest in it. The first is oncology-adjacent and largely historical: as goralatide, it was tested in the 1990s as a bone marrow protectant during chemotherapy, on the logic that temporarily holding stem cells out of S-phase would shield them from cytotoxic drugs. The second, and the reason the compound is still studied, is a large animal literature on fibrosis in the heart, kidney, lung, and liver.

Ac-SDKP is not TB-500, and the two should not be treated as interchangeable. Both derive from thymosin beta-4, but from opposite ends of the molecule and with different biology. TB-500 is marketed around the central actin-binding region — LKKTET at residues 17–22, usually described as the seven-residue LKKTETQ spanning residues 17–23, though a large share of what ships under the TB-500 name is actually full-length thymosin beta-4 — and is associated with cell migration, angiogenesis, and wound healing. Ac-SDKP is the residue 1–4 fragment, associated with anti-proliferative, anti-inflammatory, and antifibrotic signaling (Sosne et al., FASEB Journal, 2010;24(7):2144–2151). The distinction is not merely positional: the antiproliferative activity of Ac-SDKP was shown explicitly not to be mediated by a thymosin beta-4-like effect on actin assembly, and Ac-SDKP does not compete with thymosin beta-4 for binding to G-actin (Cheviron et al., Cell Proliferation, 1996;29(8):437–446). The confusion is built into the market’s own labeling — Ac-SDKP is widely catalogued as “Thymosin Beta-4 Fragment (1-4),” and listings that describe a product only as a “thymosin beta-4 fragment” do not distinguish between the two fragments at all.

How it works

• Released from thymosin beta-4 by a two-enzyme cascade. Prolyl oligopeptidase (POP) makes the cut that liberates Ac-SDKP, confirmed in kidney cortex homogenates and in rats where POP inhibitors cut endogenous Ac-SDKP in plasma, heart, and kidney (Cavasin et al., Hypertension, 2004;43(5):1140–1145). POP cannot hydrolyze peptides longer than 30 residues and thymosin beta-4 is 43, so an upstream cut is required first: meprin-alpha trims the parent to a short enough N-terminal intermediate, and incubating thymosin beta-4 with either enzyme alone releases no Ac-SDKP at all (Kumar et al., American Journal of Physiology-Renal Physiology, 2016;310(10):F1026–F1034).
• Cleared almost exclusively by ACE, and mainly by its N-domain. Angiotensin-converting enzyme has two catalytic domains, and Ac-SDKP was the first natural peptide identified as a preferential substrate of the N-terminal active site (Rousseau et al., Journal of Biological Chemistry, 1995;270(8):3656–3661; earlier degradation work in Rieger et al., Biochemical Journal, 1993;296(Pt 2):373–378). Crystal structures of the N-domain in complex with the dipeptide products of Ac-SDKP cleavage later mapped how the enzyme recognizes it (Masuyer et al., Scientific Reports, 2015;5:13742). The practical consequence is a plasma half-life of about 4.5 minutes and a strong drug interaction with ACE inhibitors — a single 50 mg oral dose of captopril in eight healthy subjects, in a double-blind placebo-controlled crossover study, produced a long-lasting 5.5-fold rise (range 4- to 8.5-fold) in plasma Ac-SDKP (Azizi et al., Journal of Clinical Investigation, 1996;97(3):839–844).
• Suppresses TGF-beta1-driven myofibroblast conversion. In human fetal cardiac fibroblasts, Ac-SDKP blocked TGF-beta1-induced differentiation into myofibroblasts, collagen production, and proliferation, and inhibited phosphorylation of Smad2 and ERK1/2 (Peng et al., American Journal of Physiology-Heart and Circulatory Physiology, 2010;298(5):H1357–H1364). This is the mechanistic core of the antifibrotic claim, and it builds on earlier work showing Ac-SDKP inhibits Smad2 phosphorylation in cardiac fibroblasts (Pokharel et al., Hypertension, 2002;40(2):155–161).
• Holds hematopoietic stem cells out of S-phase. The original described activity is reversible inhibition of stem cell and early progenitor entry into cell cycle (Lenfant et al., 1989, above), the property the 1990s chemoprotection program was built on.
• Acts through a receptor that has never been identified. High-affinity binding sites for Ac-SDKP were characterized in rat cardiac fibroblasts — a single class of sites with a dissociation constant of 3.3 nM — and localized to the myocardial interstitium using a radiolabeled analog (Zhuo et al., American Journal of Physiology-Heart and Circulatory Physiology, 2007;292(2):H984–H993), but a receptor has not been cloned, and reviews continue to name that as the field’s central open question (Kassem et al., Canadian Journal of Physiology and Pharmacology, 2019;97(7):589–599).

Research status

The evidence base is deep in animals and thin, old, and negative in humans.

Animal antifibrotic work. This is where nearly all published support sits. In rats with angiotensin II-induced hypertension, Ac-SDKP infused subcutaneously at 400 mcg/kg/day — a dose chosen because it raises plasma Ac-SDKP to roughly the level ACE inhibition produces — reproduced the anti-inflammatory and antifibrotic effects of captopril in the left ventricle, reducing cell proliferation, macrophage and mast cell infiltration, TGF-beta, connective tissue growth factor, and collagen deposition without lowering blood pressure (Rasoul et al., Journal of Hypertension, 2004;22(3):593–603). In kidney, Ac-SDKP reduced collagen and fibronectin deposition, myofibroblasts, and macrophages in ureteral obstruction models, in both wild-type and PAI-1 knockout mice; in the same study the intact parent protein plus a POP inhibitor was consistently profibrotic, while thymosin beta-4 alone promoted repair and reduced late fibrosis — and both of those parent-protein effects, unlike Ac-SDKP’s, depended on PAI-1 (Zuo et al., Kidney International, 2013;84(6):1166–1175). In the mouse bleomycin model of lung injury, it reduced mortality, inflammation, and collagen content both preventively and when started seven days after injury (Conte et al., Oncotarget, 2016;7(23):33841–33854). It has also been tested in rat traumatic brain injury, where subcutaneous treatment improved sensorimotor and spatial learning recovery (Zhang et al., Journal of Neurosurgery, 2017;126(3):782–795), and in a preclinical spinal cord injury model (Hashemizadeh et al., Neuropeptides, 2022;92:102228).

Most of this work delivered the peptide by osmotic minipump or continuous infusion, a design choice that follows from the 4.5-minute half-life. It is not universal, though: the bleomycin lung study dosed intraperitoneally on a bi-weekly schedule and still reported benefit, so “continuous delivery only” overstates the record.

Human pharmacokinetics. Real human PK exists, from the goralatide era. In six healthy volunteers and five patients receiving chemotherapy, intravenous infusion gave a mean elimination half-life of 4.5 minutes and a volume of distribution of 117 mL/kg; subcutaneous and intramuscular bioavailability were 100% and 81% respectively, with peak concentrations at roughly 16 minutes. Clearance was about half as fast in patients as in healthy volunteers, 524 versus 1,120 mL/hr/kg (Ezan et al., Drug Metabolism and Disposition, 1994;22(6):843–848).

The controlled human trial failed. Eighty-four patients with locally advanced squamous cell carcinoma of the head, neck, or esophagus were randomized in a multicenter double-blind trial comparing goralatide at 12.5 or 62.5 mcg/kg/day (days 1–4) against placebo alongside carboplatin and 5-fluorouracil, with hematologic toxicity analyzed across 221 chemotherapy cycles. There was no significant difference in mean nadir of leukocytes, granulocytes, platelets, or hemoglobin, and no significant difference in the duration of hematologic toxicity. Anemia and lymphopenia were in fact more frequent in the goralatide arm. Tolerability was reported as excellent (Cappelaere et al., Bulletin du Cancer, 1995;82(9):732–737, in French). Supporting preclinical work in mice had shown stem cell protection and an enhanced myelopoietic response to GM-CSF (Bogden et al., International Journal of Cancer, 1998;76(1):38–46), but that did not translate.

No human trial has ever tested Ac-SDKP as an antifibrotic. Registry searches return studies that measure endogenous Ac-SDKP as a pharmacodynamic or compliance marker of ACE inhibition rather than administering it, plus one completed study using the amide analog AcSDKP-NH2 as a non-radioactive glomerular filtration rate tracer (NCT01588756). A systematic review and meta-analysis of four studies covering 206 participants confirmed that ACE inhibitors raise human plasma Ac-SDKP — mean difference 5.07 pmol/mL in healthy subjects and 8.94 pmol/mL in renal failure — and framed that as the rationale for testing ACE inhibitors against fibrosis in tuberculous pericarditis (Mnguni et al., PLoS One, 2015;10(12):e0143338). That is a finding about ACE inhibitor drugs, not evidence for administered Ac-SDKP.

Ac-SDKP is not approved by any regulator, and DailyMed returns no drug label for goralatide or Ac-SDKP.

Common dosage forms

• Lyophilized powder in vials for reconstitution, the standard research-peptide presentation.
• Oral capsules, commonly 500 mcg or 250 mcg per capsule.
• Oral or sublingual liquid sprays, commonly around 500 mcg/mL in 30 mL bottles.
• Multi-peptide blends, where a thymosin beta-4 derivative is combined with other repair-oriented peptides in a single vial or capsule; in these the label often names only “thymosin beta-4” or “thymosin beta-4 fragment,” so neither the Ac-SDKP content nor the fragment identity is stated.
• Analytical-grade reference peptide sold by laboratory reagent suppliers for assay and standards use, distinct from the research-market presentations above.

Listings appear under several names — “Ac-SDKP,” “goralatide,” and “Thymosin Beta-4 Fragment (1-4),” and sometimes under TB-500 naming despite being the other fragment — which makes name-matching alone an unreliable way to tell what a vial or capsule contains. This section describes formats only and is not dosing guidance.

Key considerations

• The TB-500 confusion is the main thing to get right. Ac-SDKP and TB-500 are both thymosin beta-4 derivatives, but they are different fragments — residues 1–4 versus the LKKTET actin-binding region at residues 17–22 — with different described mechanisms, different literatures, and different molecular weights. Ac-SDKP’s antiproliferative effect was specifically shown not to run through actin assembly, so copy that attributes actin polymerization or cell-migration effects to Ac-SDKP is describing the wrong fragment. Listings that name only the parent protein are not evidence that a container holds either fragment specifically. Independent identity testing is the only way to tell, and the mass difference is large enough that a four-residue peptide is trivially distinguishable from anything built on the actin-binding region or on the full 43-residue parent.
• The only controlled trial of administered Ac-SDKP was negative, and it was in a different indication. Goralatide reached a randomized, double-blind, placebo-controlled trial for chemotherapy myeloprotection and missed on every hematologic endpoint. Nothing in the antifibrotic literature — the reason the compound is marketed today — has been tested in a human trial at all.
• The pharmacokinetics do not match the oral and sublingual formats sold. Injected peptide is well absorbed — subcutaneous bioavailability was 100% and intramuscular 81% — but the 4.5-minute half-life means a bolus produces a brief spike rather than the sustained exposure most positive animal studies used. Oral capsules and sublingual sprays are a further step removed: no oral or sublingual bioavailability data for Ac-SDKP appears in the published literature, and a four-residue peptide faces gut proteolysis before absorption.
• ACE inhibitors are a direct interaction, in both directions. ACE is the clearance pathway, so anyone taking an ACE inhibitor already has severalfold-elevated endogenous Ac-SDKP, and exogenous peptide is cleared by the same enzyme that the drug blocks. Urinary Ac-SDKP is also used as an objective compliance marker for ACE inhibitor therapy (Azizi et al., Diabetes Care, 2006;29(6):1331–1336), so exogenous administration would confound that assay.
• Not every described effect is a benefit. Ac-SDKP is characterized as pro-angiogenic as well as antifibrotic (Kumar and Yin, Pharmacological Research, 2018;134:268–279), and its founding activity is suppression of hematopoietic stem cell cycling. Both properties cut in more than one direction depending on context, and no long-term human safety data exists for administered Ac-SDKP at any dose.
• The receptor is unknown and the pathway is not fully mapped. Binding sites have been characterized but never cloned, which means dose-response, tissue selectivity, and off-target behavior in humans are all unresolved.