Ac-SDKP

What is Ac-SDKP?

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is an endogenous tetrapeptide produced in the body by enzymatic cleavage from the N-terminus of thymosin β4. It circulates at low nanomolar concentrations in plasma and is degraded almost exclusively by the N-terminal active site of angiotensin-converting enzyme (ACE) — which is why ACE inhibitors raise circulating Ac-SDKP several-fold. In the 1990s, a synthetic form was developed under the name goralatide (Seraspenide) as a chemoprotective agent — meant to reversibly arrest hematopoietic stem-cell proliferation during chemotherapy to spare bone marrow. That development program did not yield an approved product. More recent research has shifted focus to Ac-SDKP's broad antifibrotic activity across cardiac, renal, pulmonary, and hepatic tissue, and to its role as a pharmacodynamic biomarker of ACE activity.

What Ac-SDKP Is Investigated For

Ac-SDKP is primarily a research molecule with two historical through-lines. The first is its 1990s development as goralatide, a chemoprotective agent meant to reversibly quiesce hematopoietic stem cells during cytotoxic chemotherapy — an idea that made it into Phase 2 but never produced an approved product. The second, and the focus of current research, is its antifibrotic activity. Preclinical models across cardiac, renal, pulmonary, and hepatic tissue consistently show that Ac-SDKP reduces collagen deposition, inhibits TGF-β/Smad signaling, suppresses endothelial-to-mesenchymal transition, and attenuates inflammation-driven fibrotic remodeling. The clearest clinical footprint today is as a biomarker: circulating Ac-SDKP rises several-fold in patients on ACE inhibitors (because ACE is its dominant catabolic enzyme), and it is used pharmacologically to verify ACEi activity. There is no approved Ac-SDKP therapeutic, no established clinical dose for antifibrotic indications, and no human safety database beyond the historical goralatide trials. Products sold online as "Ac-SDKP" are research chemicals without validated human pharmacology.

History & Discovery

Ac-SDKP was first described in the 1980s in bone marrow research as an endogenous inhibitor of hematopoietic stem-cell proliferation. It was purified in 1989 from fetal calf bone marrow by a team at the CNRS Institut de Chimie des Substances Naturelles in Gif-sur-Yvette, France, and carried into the clinic through the 1990s as goralatide (Seraspenide) for chemoprotection — the idea that reversibly arresting marrow cycling during chemotherapy could reduce myelotoxicity. Two randomized human trials were run. A 53-patient phase I-II crossover study at Institut Gustave-Roussy in patients on cytarabine or ifosfamide reported significant protection of blood counts and no toxicity. But the larger confirmatory trial — 84 patients with head-and-neck or esophageal cancer on carboplatin plus fluorouracil, with 221 chemotherapy cycles analysed — found no significant difference versus placebo in the nadir of white cells, granulocytes, platelets, or hemoglobin, and the program did not proceed to approval. A parallel research line characterized Ac-SDKP as an ACE substrate, and by the early 2000s the antifibrotic activity across cardiac, renal, pulmonary, and hepatic tissue had been described in detail, largely through work from Oscar Carretero's group at Henry Ford Hospital and collaborators. The modern research footprint is dominated by this antifibrotic and ACE-biomarker literature rather than the original hematopoietic framing.

How It Works

Your body cleaves a small four-amino-acid peptide — Ac-SDKP — from a larger regenerative protein called thymosin β4. In animal studies, Ac-SDKP reduces scarring (fibrosis) in the heart, kidneys, lungs, and liver by dampening the signals that tell tissue to lay down collagen. In people, the main reason Ac-SDKP matters clinically today is that ACE inhibitors like lisinopril raise its levels several-fold, and part of the long-term protective effect of ACE inhibitors may come from that elevation. No Ac-SDKP drug is approved.

Ac-SDKP is generated from thymosin β4 by sequential action of meprin-α and prolyl oligopeptidase (POP). Because POP can only cut peptides shorter than about 30 amino acids and thymosin β4 is 43 residues long, meprin-α has to shorten the parent protein first; POP, which cleaves after proline, then releases the tetrapeptide. Ac-SDKP circulates at low nanomolar concentrations and is degraded almost exclusively by angiotensin-converting enzyme (ACE). Both of ACE's active sites can cut it, but the N-terminal site does so about 50 times faster, which made Ac-SDKP the first natural substrate described as specific to that domain. The result is a very short plasma half-life — about 4.5 minutes in healthy volunteers after an intravenous infusion stops. Pharmacologically, Ac-SDKP's antifibrotic mechanism is multimodal: it inhibits TGF-β1 signaling by suppressing phosphorylation and nuclear translocation of Smad2/3, blocks endothelial-to-mesenchymal transition (EndMT) in cardiac and renal endothelium, reduces infiltration of pro-inflammatory M1 macrophages (in one post-infarction study without affecting M2 macrophages), and inhibits collagen type I and III deposition in multiple organ models. In hematopoietic biology, Ac-SDKP reversibly arrests cycling of primitive hematopoietic stem cells in the G1 phase, which was the basis for its 1990s development as a chemoprotective agent (goralatide). The relationship to ACE is bidirectional: ACE degrades Ac-SDKP, so ACE inhibitors elevate plasma Ac-SDKP, and elevated Ac-SDKP is considered a contributor to the antifibrotic effects of ACE inhibitors that are not explained by angiotensin II reduction or bradykinin accumulation alone. The antifibrotic mechanism now reaches into RNA epigenetics. A 2022 liver-fibrosis study first tied Ac-SDKP to the N6-methyladenosine (m6A) machinery through the WTAP/m6A/Ptch1 axis and Hedgehog signaling, and a 2026 FASEB J study carried the theme into the lung: Ac-SDKP attenuates silica-induced pulmonary fibrosis by suppressing the m6A demethylase ALKBH1, which otherwise strips m6A from pri-miR-129-5p and blocks DGCR8-mediated processing into the mature microRNA. Silicosis is not a new model for this peptide — the Ac-SDKP silicosis literature runs from 2008 to the present and takes in EGFR/STAT3 signaling and p38MAPK/mTOR-dependent autophagy alongside the m6A axis.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Ac-SDKP:

• 01No specific high-affinity Ac-SDKP receptor has been conclusively identified — much of its activity is inferred from pathway modulation rather than canonical GPCR pharmacology.
• 02Whether chronic exogenous Ac-SDKP dosing replicates the antifibrotic effects attributed to ACE-inhibitor-mediated endogenous elevation has not been directly tested in humans.
• 03Long-term hematopoietic effects of sustained exogenous Ac-SDKP exposure in patients not undergoing chemotherapy are uncharacterized.
• 04Comparative efficacy against approved antifibrotics (pirfenidone, nintedanib) in idiopathic pulmonary fibrosis has not been studied. The one combination tested so far is in the heart, where adding Ac-SDKP to eplerenone in angiotensin II-driven cardiac injury in mice gave additive rather than synergistic improvement.
• 05Delivery is the binding constraint. The native peptide is gone from plasma within minutes, so essentially every preclinical antifibrotic result relies on continuous osmotic-minipump infusion. Five workarounds now exist. A D-amino-acid-substituted analogue resists ACE and outperformed native Ac-SDKP against liver fibrosis in rats. An amidated analogue is stable enough that Assistance Publique-Hôpitaux de Paris carried it through a Phase 1/2 study which completed in 2015 with 100 participants — 100 micrograms intravenously, benchmarked against inulin and chromium-EDTA — though as a glomerular-filtration marker rather than as a therapy (NCT01588756). More recent work has moved from analogues to carriers: cholesterol-anchored platelet-derived small extracellular vesicles, loaded at 93.7 to 97.0 percent efficiency, suppressed cytokine secretion more effectively than an equal concentration of free peptide; PAMAM-based nanoassemblies grown onto a device surface promoted endothelial regeneration and suppressed neointimal hyperplasia in rats; and a cellulose-based adhesive hydrogel lowered scar index and collagen disorganization in a rabbit ear model. None of the five has been tested as a chronic antifibrotic therapy in humans.
• 06Whether Ac-SDKP is uniformly protective is now in question. A 2026 chronic-kidney-disease study found it suppressed pericyte-to-myofibroblast transition and restored pericyte-derived VEGF through the VEGF/FGFR1 axis, but worsened apoptosis in already-injured tubular cells in culture — an effect the authors traced to its concurrent inhibition of the Akt survival pathway rather than to FGFR1, with the FGFR1 upregulation acting as a compensatory rescue rather than as the harm. Timing mattered as well: dosing from week three mitigated fibrosis and preserved capillary integrity in vivo, while starting at week four was less effective. Whether this compartment-specific split holds outside that model is unresolved.
• 07The cleanest translational route may not involve dosing Ac-SDKP at all. Current ACE inhibitors block both of the enzyme's active sites, and a 2026 structural study of enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat argued for N-domain-selective inhibitors that would raise Ac-SDKP for an antifibrotic effect without suppressing the conversion of angiotensin I — noting that non-selective inhibition produces serious side effects in roughly 20 to 25 percent of patients. No N-selective inhibitor has reached the clinic.

Forms & Administration

Ac-SDKP is not available as an approved therapy. In preclinical antifibrotic studies, it is most commonly delivered by osmotic minipump infusion because of its short plasma half-life (minutes, owing to rapid ACE-mediated degradation). The historical goralatide trials used intravenous infusion, and the human pharmacokinetic study also tested subcutaneous and intramuscular injection: bioavailability was 100% subcutaneously and 81% intramuscularly, with peak levels about 16 minutes after injection. None of those routes solves the underlying problem, which is that plasma levels collapse within minutes once dosing stops. The practical clinical path to elevating endogenous Ac-SDKP today is through ACE inhibitor therapy, which raises plasma levels roughly 4- to 5.5-fold as a pharmacologic side effect.

Common Questions

Who Ac-SDKP Is NOT For

Drug & Supplement Interactions

The most characterized interaction is with ACE inhibitors (lisinopril, ramipril, captopril, enalapril, etc.), which raise plasma Ac-SDKP roughly 4- to 5.5-fold by blocking its primary catabolic pathway. This is a pharmacokinetic fact rather than a known adverse interaction, but any clinical dosing of exogenous Ac-SDKP would need to account for it. Angiotensin receptor blockers act downstream of ACE and are not known to raise Ac-SDKP on their own. In a crossover trial in chronic kidney disease, adding valsartan to lisinopril did not change the picture, but sodium restriction on top of either regimen raised circulating Ac-SDKP further. Theoretical interactions with other antifibrotic or cytotoxic therapies exist but are uncharacterized, and Ac-SDKP's effect on monocyte/macrophage polarization raises theoretical considerations around combination with immunomodulators, though none of this has been studied clinically.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions