TB-4 Fragment (Ac-SDKP)
Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a naturally occurring tetrapeptide released from thymosin beta-4 by prolyl oligopeptidase. It is a potent anti-fibrotic agent with significant research in cardiac and renal fibrosis, hematopoietic stem cell regulation, and inflammation.
Overview
Ac-SDKP was first identified as a hematopoietic stem cell inhibitor in 1990 by Lenfant et al., who demonstrated that the peptide prevents entry of pluripotent hematopoietic stem cells into S-phase of the cell cycle. This protective function shields stem cells from cytotoxic damage during chemotherapy. Subsequent research revealed that Ac-SDKP is an endogenous substrate of ACE, and that ACE inhibitors—among the most widely prescribed cardiovascular drugs—exert part of their anti-fibrotic benefit by raising Ac-SDKP levels. This discovery reframed understanding of ACE inhibitor pharmacology and established Ac-SDKP as a key mediator of tissue homeostasis.
Mechanism of Action
Anti-Fibrotic Signaling: Ac-SDKP inhibits fibroblast proliferation and collagen synthesis through suppression of TGF-beta/Smad signaling. It blocks Smad2 phosphorylation and nuclear translocation, reducing transcription of collagen type I and type III genes. Kanasaki et al. (2003) demonstrated that Ac-SDKP inhibits TGF-beta-induced collagen production in cardiac fibroblasts by interfering with Smad signaling.
ACE-Regulated Metabolism: ACE is the primary enzyme responsible for Ac-SDKP degradation in vivo. Normal plasma Ac-SDKP levels are approximately 1-2 nM. ACE inhibitor administration increases these levels 4-5 fold. Rhaleb et al. (2001) showed that the anti-fibrotic effects of ACE inhibitors are partially mediated through Ac-SDKP accumulation.
Hematopoietic Stem Cell Regulation: Ac-SDKP reversibly inhibits entry of hematopoietic stem cells into S-phase, maintaining them in G0/G1 quiescence. This protects the stem cell pool from cycle-dependent cytotoxic agents without impairing differentiation capacity upon peptide withdrawal.
Anti-Inflammatory Activity: Ac-SDKP inhibits macrophage activation and reduces expression of pro-inflammatory cytokines including TNF-alpha and IL-1beta, contributing to its organ-protective effects beyond direct anti-fibrotic action.
Reconstitution Calculator
TB-4 Fragment (Ac-SDKP)
**TB-4 Fragment (Ac-SDKP)** is an endogenous tetrapeptide corresponding to the N
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Research
Anti-Inflammatory Research
Ac-SDKP reduces macrophage infiltration in fibrotic tissues and suppresses inflammatory cytokine expression. In cardiac inflammation models, Ac-SDKP inhibits NF-kappaB activation in macrophages and reduces monocyte chemoattractant protein-1 (MCP-1) levels, limiting inflammatory cell recruitment to damaged tissue.
Cardiac Anti-Fibrotic Effects
The most extensively studied property of Ac-SDKP is its ability to prevent and reverse cardiac fibrosis. Peng et al. (2003) demonstrated that Ac-SDKP prevents collagen deposition in the left ventricle of rats with aldosterone-salt-induced hypertension. Rasoul et al. (2004) showed that Ac-SDKP infusion reduces cardiac fibrosis and improves diastolic function in hypertensive rats independently of blood pressure reduction.
Peng et al. (2010) further demonstrated that Ac-SDKP reverses established cardiac fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, indicating therapeutic potential beyond prevention. Zuo et al. (2014) showed that Ac-SDKP attenuates cardiac fibrosis via suppression of the TGF-beta1/Smad2 pathway and inhibition of myofibroblast differentiation in a pressure-overload heart failure model.
Renal Anti-Fibrotic Effects
Ac-SDKP demonstrates significant renal protection in models of kidney fibrosis. Kanasaki et al. (2003) showed that Ac-SDKP inhibits renal fibroblast collagen production via Smad pathway interference. In diabetic nephropathy models, Ac-SDKP administration reduces glomerulosclerosis and tubulointerstitial fibrosis. The peptide also inhibits endothelial-to-mesenchymal transition (EndMT), a process contributing to kidney fibrosis.
Hematopoietic Stem Cell Protection
Lenfant et al. (1990) first demonstrated that Ac-SDKP inhibits proliferation of murine pluripotent hematopoietic stem cells. Azizi et al. (1996) confirmed that ACE inhibitors increase plasma Ac-SDKP levels in humans, suggesting a clinical mechanism for stem cell protection during concurrent chemotherapy and ACE inhibitor use.
Safety Profile
Ac-SDKP is an endogenous peptide continuously present in normal human plasma, conferring a favorable baseline safety profile. In preclinical studies, chronic Ac-SDKP infusion at supraphysiological doses does not produce hypotension, organ toxicity, or immunosuppression. Since ACE inhibitors raise Ac-SDKP levels as part of their mechanism, millions of patients effectively experience elevated Ac-SDKP chronically without attributable adverse effects. Theoretical considerations include effects on hematopoiesis at very high doses, though stem cell inhibition is reversible upon peptide withdrawal.
Pharmacokinetic Profile
TB-4 Fragment (Ac-SDKP) — Pharmacokinetic Curve
Molecular Structure
- Weight
- 487.5 Da
- CAS
- 110942-02-4
Research Protocols
subcutaneous Injection
Clinical Research Protocols - Dosing (preclinical): Most rodent studies use 400-800 microg/kg/day via subcutaneous osmotic minipump infusion over 2-8 weeks. - Routes: Subcutaneous infusion (osmotic pump), intraperitoneal injection.
intraperitoneal Injection
- Routes: Subcutaneous infusion (osmotic pump), intraperitoneal injection.
Interactions
Peptide Interactions
Theoretical complementarity—Ac-SDKP targets fibrosis reduction while BPC-157 promotes angiogenesis and tissue regeneration. No direct combination studies published.
What to Expect
What to Expect
Rapid onset expected; half-life of Very short (~4.5 minutes in plasma) due to rapid ACE-mediated hydrolysis. indicates fast-acting pharmacokinetics
Dosing (preclinical): Most rodent studies use 400-800 microg/kg/day via subcutaneous osmotic minipump infusion over 2-8 weeks.
Due to short half-life (Very short (~4.5 minutes in plasma) due to rapid ACE-mediated hydrolysis.
Regular administration schedule required; effects are dose-dependent and do not persist between doses
Quality Indicators
What to look for
- Naturally occurring compound
- Extensive peer-reviewed research base
Frequently Asked Questions
References (10)
- [7]Peng H, Xu J, Yang XP, et al Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension Hypertension (2010)
- [9]
- [10]
- [8]Zuo L, et al Ac-SDKP attenuates cardiac fibrosis in pressure-overload heart failure via TGF-beta1/Smad pathway Int J Cardiol (2014)
- [1]Lenfant M, Wdzieczak-Bakala J, Guittet E, et al Inhibitor of hematopoietic pluripotent stem cell proliferation: purification and determination of its structure PNAS (1990)
- [2]Azizi M, Rousseau A, Ezan E, et al Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline J Clin Invest (1996)
- [3]Rhaleb NE, Peng H, Harding P, et al Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts Hypertension (2001)
- [4]Peng H, Carretero OA, Raij L, et al Antifibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline on the heart and kidney in aldosterone-salt hypertensive rats Hypertension (2003)
- [5]Kanasaki K, Koya D, Sugimoto T, et al N-Acetyl-seryl-aspartyl-lysyl-proline inhibits TGF-beta-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells J Am Soc Nephrol (2003)
- [6]Rasoul S, Bhagwandien R, et al Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension J Hypertens (2004)
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