In vitro
This study presents a novel chemical synthesis methodology called Aryl Selenoester Aminolysis Ligation (ASAL), designed to overcome key limitations of existing peptide manufacturing approaches. Traditional solid-phase peptide synthesis (SPPS) is costly and resource-intensive, while tag-assisted peptide synthesis (TAPS) is generally restricted to peptides of 20 residues or fewer. Fragment condensation methods for longer peptides often produce problematic epimerization (structural errors). The researchers integrated ASAL into a TAPS workflow to enable convergent, fragment-based assembly of longer therapeutic peptides in solution. They demonstrated the platform by successfully synthesizing three clinically relevant peptides of increasing complexity: teriparatide (34 residues, used in osteoporosis treatment), a sulfated thrombin-inhibiting anticoagulant TTI (32 residues), and tirzepatide (39 residues, used for type 2 diabetes and weight management). The method reportedly minimized epimerization, reduced reagent and solvent consumption, and showed promise for scalability. Limitations include the study being purely a chemistry/methods paper with no biological testing in cells, animals, or humans — all findings are based on synthetic yield, purity, and chemical characterization metrics alone.
Journal of the American Chemical Society · Jun 2026DOI ↗ In vitro
This study investigated whether five FDA-approved glucagon-like peptide-1 receptor agonists (GLP-1RAs) — semaglutide, tirzepatide, liraglutide, and two others — could directly inhibit the aggregation of the 42-residue amyloid-β peptide (Aβ42), a key process implicated in Alzheimer's disease (AD). Using in vitro aggregation kinetics and microscopic analysis, researchers found that semaglutide, tirzepatide, and liraglutide inhibited Aβ42 aggregation, primarily by targeting the primary nucleation step — the initial formation of amyloid seeds. Semaglutide and tirzepatide delayed aggregation with submicromolar potency, while liraglutide showed the strongest suppression of primary nucleation and additionally modestly inhibited secondary nucleation. Liraglutide also altered fibril structure — producing less mature, more tortuous, and longer fibrils — and reduced the ability of fibrils to self-replicate (template). The study was conducted entirely in vitro (no cell, animal, or human data), which is a significant limitation for clinical translation. The authors conclude that certain GLP-1RAs can directly interfere with molecular steps of Aβ42 aggregation, and call for further studies to determine whether these mechanisms contribute to potential AD-protective effects observed in preclinical and clinical research.
Journal of the American Chemical Society · May 2026DOI ↗ In vitro
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Journal of cachexia, sarcopenia and muscle · Apr 2026DOI ↗ In vitro
This study developed and validated a stability-indicating High-Performance Liquid Chromatography (HPLC) method for the simultaneous quantification of two GLP-1 receptor agonists — Semaglutide (SEM) and Tirzepatide (TIR) — used in the treatment of type 2 diabetes and obesity. The method employed a C18 column with an isocratic mobile phase of 0.1% formic acid and acetonitrile (30:70), achieving rapid separation with retention times of 1.42 min for SEM and 1.68 min for TIR. The method was validated per ICH guidelines, demonstrating strong linearity (1–500 µg/mL, r > 0.9999), sensitivity (LOD: 10 ng/mL for TIR; 16 ng/mL for SEM), accuracy, and precision. The method successfully resolved both compounds from degradation products generated under acidic, basic, oxidative, and photolytic stress conditions. It was also applied to bulk drug, pharmaceutical dosage forms, and spiked rat plasma. A comprehensive six-pronged sustainability assessment was performed using nine analytical greenness, whiteness, blueness, and violet innovation tools. A key limitation is that the plasma work used spiked rat samples rather than real patient samples, meaning no clinical or pharmacokinetic conclusions about humans can be drawn.
BMC chemistry · Jan 2026DOI ↗