Stylianaki, E.-A. | Search bioRxiv

bioRxiv2025

An aerosolised dual-action Autotaxin inhibitor- PPARγ agonist for the treatment of pulmonary fibrosis

Fibrosis is a significant mortality factor and health concern, promoting organ malfunction as well as immune and chemical resistance. Among the different fibroproliferative diseases, idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic interstitial lung disease (ILD) with limited therapeutic options. Autotaxin (ATX), an established therapeutic target in IPF, is a secreted lysophospholipase D that catalyses the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signalling phospholipid. The many pathologic effects of LPA in the lung include the suppression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a therapeutic target in metabolic disorders, which are frequent comorbidities of IPF associated with unfavourable prognosis. In this report, we introduce EL244, the first-in-class dual ATX inhibitor and PPAR{gamma} agonist, which is endowed with drug-like properties. Developed through chemoinformatic repositioning, innovative rational design, targeted synthesis and pharmacological characterization, EL244 exhibited favourable ADMET and PK/PD profiles. Remarkably, EL244 inhalation, which alleviates systemic toxicity concerns, decreased pulmonary LPA levels and related effects in pulmonary cells, and attenuated bleomycin (BLM)-induced pulmonary fibrosis, restoring respiratory functions. Therefore, EL244 emerges as a promising candidate for the inhaled treatment of IPF and ILDs.

pathology↗

bioRxiv2024

ERAP1 activity modulates the immunopeptidome but also affects the proteome, metabolism and stress responses in cancer cells

Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) metabolizes peptides inside the ER and shapes the peptide repertoire available for binding to Major Histocompatibility Complex Class I molecules (MHC-I). Moreover, it may have additional effects on cellular homeostasis, which have not been explored. To address these questions, we used both genetic silencing of ERAP1 expression as well as treatment with a selective allosteric ERAP1 inhibitor to probe changes in the immunopeptidome and proteome of the A375 melanoma cancer cell line. We observed significant immunopeptidome shifts with both methods of functional ERAP1 disruption, which were distinct for each method. Both methods of inhibition led to an enhancement, albeit slight, in tumor cell killing by stimulated human PBMCs and in significant proteomic alterations in pathways related to metabolism and cellular stress. Similar proteomic changes were also observed in the leukemia cell line THP-1. Biochemical analyses suggested that ERAP1 inhibition affected sensitivity to ER stress, reactive oxygen species production and mitochondrial metabolism. Although the proteomics shifts were significant, their potential in shaping immunopeptidome shifts was limited since only 15.8% of differentially presented peptides belonged to proteins with altered expression and only 5.0% of proteins with altered expression were represented in the immunopeptidome shifts. Taken together, our findings suggest that modulation of ERAP1 activity can generate unique immunopeptidomes, mainly due to altered peptide processing in the ER, but also induce changes in the cellular proteome and metabolic state which may have further effects on tumor cells.

biochemistry↗