Ac-SDKP vs Larazotide

Inhibits hematopoietic stem cell entry into S-phase. Blocks TGF-β1-mediated fibroblast activation, reducing collagen deposition. Promotes angiogenesis via VEGF upregulation. Regulated in vivo by ACE enzyme.

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is an endogenous tetrapeptide generated from the N-terminus of thymosin beta-4 by the enzyme prolyl oligopeptidase, with further regulation by angiotensin-converting enzyme (ACE), and is characterized by roles in hematopoietic progenitor regulation and anti-fibrotic signaling in renal, cardiac, and vascular tissue. Ac-SDKP inhibits collagen synthesis and fibroblast proliferation, reduces TGF-beta-1-mediated fibrotic signaling, and promotes anti-inflammatory macrophage polarization in preclinical models, suggesting a role in tissue homeostasis downstream of the thymosin beta-4 pathway. Preclinical studies in rodent models of renal fibrosis and systemic lupus erythematosus — predominantly from the NIH-funded Rhaleb and Carretero laboratory at Henry Ford Health — have demonstrated that exogenous Ac-SDKP reduces collagen deposition and inflammatory infiltrate; no human clinical trials have been completed or indexed in PubMed. Ac-SDKP has no FDA approval and no approved indication in any jurisdiction; it is studied as a research compound with a plausible anti-fibrotic mechanism and consistent preclinical evidence, but extrapolation of rodent findings to human therapeutic outcomes has not been validated by any clinical investigation.

Synthetic octapeptide that prevents zonulin-mediated tight junction opening; maintains intestinal epithelial barrier integrity

Larazotide acetate (AT-1001) is a synthetic octapeptide zonulin antagonist that reduces intestinal permeability by blocking zonulin-mediated disassembly of intestinal epithelial tight junctions, studied as an adjunctive treatment to reduce symptom burden in celiac disease patients during inadvertent or deliberate gluten exposure. By inhibiting zonulin receptor signaling, larazotide prevents the disruption of tight junction proteins — including occludin and claudins — that would otherwise permit immunogenic gluten peptides to traverse the epithelial barrier and trigger the CD4+ T-cell-mediated mucosal injury characteristic of active celiac disease. A Phase 2 randomized, double-blind trial published in The American Journal of Gastroenterology demonstrated that larazotide acetate reduced activation of celiac disease during gluten challenge; however, the Phase 3 trial published in Gastroenterology, designed to evaluate larazotide for persistent symptoms in celiac disease patients already following a gluten-free diet, did not meet its primary endpoint. Larazotide has not received FDA approval; no NDA has been filed following the Phase 3 outcome, and it remains an investigational compound with no approved indication.