AC-SDKP

AC-SDKP (N-Acetyl-Ser-Asp-Lys-Pro) is an endogenous tetrapeptide derived from thymosin β4 through enzymatic processing by meprin-α and prolyl oligopeptidase, subsequently degraded by the N-terminal domain of angiotensin-converting enzyme (ACE). This naturally occurring peptide functions as a negative regulator of hematopoietic stem cell differentiation and demonstrates potent anti-fibrotic, anti-inflammatory, and pro-angiogenic properties across multiple organ systems including the heart, kidneys, lungs, and liver. ACE inhibitors prevent AC-SDKP degradation, raising circulating levels approximately 5-fold, which contributes to their cardiovascular protective effects beyond traditional angiotensin II blockade. Extensive preclinical research over the past 20 years has established AC-SDKP's therapeutic potential for treating fibrotic diseases, with mechanisms involving TGF-β/Smad2 pathway suppression, inhibition of myofibroblast differentiation, and promotion of endothelial function.

Anti-Fibrotic Effects Across Multiple Organs

AC-SDKP demonstrates powerful anti-fibrotic activity in cardiac, renal, pulmonary, and hepatic tissues through multiple mechanisms ^[1][2][3]. The peptide inhibits TGF-β-induced myofibroblast differentiation and collagen synthesis, reducing fibrosis markers including α-smooth muscle actin (α-SMA) and extracellular matrix deposition ^[4][5][6]. In preclinical models, AC-SDKP significantly decreased cardiac interstitial and perivascular fibrosis while partially restoring diastolic function in diabetic cardiomyopathy ^[7]. The compound suppresses phosphorylation and nuclear translocation of Smad2 in cardiac fibroblasts, representing a novel ACE-independent pathway for reducing organ fibrosis ^[8].

Cardiovascular Protection and Cardiac Remodeling

Extensive research demonstrates AC-SDKP's cardioprotective effects in various injury models including myocardial infarction, hypertension-induced damage, and radiation-induced cardiomyopathy ^[9][10][11]. The peptide reduces inflammatory cell infiltration, decreases TGF-β expression, and inhibits cardiac cell proliferation, particularly fibroblasts ^[12]. In radiation-induced heart damage, AC-SDKP strongly inhibited macrophage infiltration, fibrosis, and cardiomyocyte apoptosis by suppressing galectin-3 (Mac-2), a key mediator of cardiac fibrosis ^[10]. Treatment preserves cardiac contractile mechanisms by maintaining SERCA2 expression, indicating protection of calcium homeostasis ^[1].

Renal Protection and Diabetic Nephropathy

AC-SDKP shows exceptional promise for treating kidney fibrosis in diabetes, with oral administration ameliorating both glomerulosclerosis and tubulointerstitial fibrosis in type 1 and type 2 diabetic mouse models ^[13][14]. The peptide targets the endothelial-mesenchymal transition program through induction of endothelial fibroblast growth factor receptor signaling, suppressing renal fibroblast proliferation ^[14]. Combination therapy with AC-SDKP and ACE inhibitors restored antifibrotic microRNA levels (miR-29, let-7) to normal or higher values, suggesting synergistic therapeutic potential ^[13]. The compound functions as both a therapeutic agent and potential biomarker for kidney injury progression ^[14].

Pulmonary Anti-Fibrotic Activity

In bleomycin-induced pulmonary fibrosis models, AC-SDKP demonstrated both preventive and therapeutic efficacy, significantly decreasing mortality, weight loss, inflammation, lung damage, and fibrosis . The peptide reduced IL-17 and TGF-β expression while decreasing α-SMA expression, suppressing myofibroblast differentiation . In silicosis models, AC-SDKP inhibited lung fibroblast proliferation and collagen deposition through regulation of acetylated α-tubulin and modulation of HDAC6 and α-TAT1 enzymes . These findings support clinical translation for treating various pulmonary fibrotic diseases.

Anti-Inflammatory and Pro-Angiogenic Properties

AC-SDKP exhibits immunomodulatory effects by reducing inflammation across cardiovascular, renal, and cerebral tissues independent of blood pressure regulation . The peptide inhibits interleukin-1β-mediated matrix metalloproteinase activation in cardiac fibroblasts, normalizing MMP-2, MMP-9, and MMP-13 activity while elevating tissue inhibitor levels (TIMP-1, TIMP-2) through MAPK and NFκB pathway suppression . As a pro-angiogenic agent, AC-SDKP promotes endothelial cell migration and myocyte survival in infarcted myocardium, facilitating cardiac repair and promoting angiogenesis in both myocardial infarction and limb ischemia models .

ACE Inhibitor Synergy and Novel Therapeutic Mechanism

AC-SDKP mediates important cardiovascular benefits of ACE inhibitor therapy beyond traditional angiotensin II blockade ^[12]. ACE inhibitors prevent AC-SDKP degradation by the N-terminal ACE domain, raising plasma and tissue concentrations approximately 5-fold ^[12]. This represents a distinct mechanism contributing to the cardiac antifibrotic effects of ACE inhibitors, with studies demonstrating that antibody neutralization of AC-SDKP blocked the beneficial effects of ACE inhibition on cardiac remodeling ^[12]. The specific hydrolysis of AC-SDKP by the N-domain of ACE with 40-fold selectivity provides opportunities for designing domain-selective ACE inhibitors or ACE-resistant AC-SDKP analogues for enhanced therapeutic efficacy ^[1].

Endogenous Nature and Favorable Safety Profile

AC-SDKP is an endogenous tetrapeptide naturally present in human plasma, organs, and biological fluids, including bone marrow, lungs, kidneys, heart, and circulating mononuclear cells . As a naturally occurring peptide generated from the precursor protein thymosin-β4 through normal physiological processes involving meprin-α and prolyl oligopeptidase, AC-SDKP exhibits minimal toxicity concerns in preclinical studies . The peptide's endogenous nature contributes to its favorable safety profile, as the body naturally produces and regulates AC-SDKP levels under normal conditions.

Preclinical Toxicity and Cell Viability Studies

Preclinical investigations have demonstrated minimal toxicity and maximum cell viability at therapeutic concentrations. Studies examining AC-SDKP effects on human cardiac fibroblasts found minimal toxicity and maximum cell viability at 0.25 μg/mL for 24-hour treatment ^[14]. Historical research on AC-SDKP as a tetrapeptide inhibitor of hematopoietic stem cell proliferation reported amelioration of chemotherapy-induced toxicity when co-treated with AC-SDKP, suggesting protective rather than toxic effects in stressed cellular environments.

Multiple Organ System Safety

Extensive preclinical studies spanning over 20 years in heart, kidney, brain, and lung injury models have consistently shown that AC-SDKP treatment ameliorates end-organ damage by reducing inflammation, fibrosis, and promoting angiogenesis without significant adverse effects . In bleomycin-induced pulmonary fibrosis models, mice receiving AC-SDKP showed significantly decreased mortality, improved weight maintenance, and reduced organ damage compared to untreated controls, indicating therapeutic benefit without additional toxicity . Similarly, diabetic animal models treated with oral AC-SDKP demonstrated improved kidney function markers without adverse effects ^[13].

Blood Pressure Independence and Cardiovascular Safety

Importantly, the protective effects of AC-SDKP on cardiovascular, renal, and cerebral tissues occur independently of blood pressure regulation, suggesting a direct tissue-protective mechanism rather than hemodynamic effects . This blood pressure-independent action profile may reduce concerns about hypotensive adverse events that often complicate cardiovascular therapeutics. Clinical studies involving ACE inhibitor therapy, which increases plasma and tissue AC-SDKP concentrations approximately 5-fold, have not identified AC-SDKP-specific safety concerns, as elevated levels appear to contribute to therapeutic benefits ^[12].

Clinical Translation Considerations

While extensive preclinical data supports AC-SDKP's favorable safety profile, formal phase I/II/III human clinical trials specifically evaluating exogenously administered AC-SDKP are limited. The available literature from ACE inhibitor trials (which elevate endogenous AC-SDKP) and preclinical studies suggest the peptide is well-tolerated, but comprehensive human safety, pharmacokinetic, and dose-ranging studies are needed for clinical translation as a standalone therapeutic agent ^[1][14]. The first reports demonstrating both preventive and therapeutic effects in pulmonary fibrosis models support the need for further preclinical and clinical investigation .