AC-SDKP

Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro, historical name goralatide) is an endogenous tetrapeptide cleaved by prolyl oligopeptidase from the N-terminus of thymosin β4. Unlike most research peptides, its pharmacology is defined not by a receptor (a specific Ac-SDKP receptor has still not been identified) but by the enzyme that degrades it: Ac-SDKP is a natural, highly specific substrate of the N-terminal active site of angiotensin-converting enzyme (ACE).

This very fact made the peptide well known. Because ACE is the main route of its degradation, therapy with ACE inhibitors raises the plasma concentration of Ac-SDKP roughly fivefold. This gave rise to the hypothesis that part of the antifibrotic effect of ACE inhibitors is mediated by the accumulation of Ac-SDKP, and not only by the lowering of angiotensin II.

What the research shows. In preclinical models (rodents) Ac-SDKP suppresses Smad2 phosphorylation in cardiac fibroblasts, that is, it intervenes in TGF-β1 signalling, a central pathway of fibrogenesis. Reduced fibrosis has been described in models of the heart, kidney and lung (the bleomycin model). Importantly: no clinical trial of Ac-SDKP for an antifibrotic indication has been carried out in humans. These are preclinical data.

A history worth knowing. Ac-SDKP has already been studied in humans, but for a completely different indication. In the 1990s, under the name goralatide, it was studied as a chemoprotectant: the peptide reversibly holds haematopoietic stem cells out of S phase and thereby protects the bone marrow from cytostatics. Phase I and II studies were run, but the drug never reached registration. The key reason Ac-SDKP did not become a medicine is its half-life of about 4 to 5 minutes: the same ACE destroys it almost instantly. So the modern direction is not to administer the peptide but to create N-domain-selective ACE inhibitors that raise the body's own Ac-SDKP without blocking bradykinin metabolism.

Ac-SDKP is of interest for laboratory research precisely as a tool for studying the thymosin β4 → prolyl oligopeptidase → Ac-SDKP → ACE N-domain axis, and as a positive control in experiments on TGF-β1/Smad signalling.

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