Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects most adults worldwide. Although frequently associated with acute hepatitis, no specific treatment for EBV-induced hepatitis currently exists. Using murine γ-herpesvirus 68 (MHV68) infection in mice, which is a well-established murine model for EBV infection, we previously demonstrated that MHV68-induced hepatitis is mediated via the Toll-like receptor 4 (TLR4) signaling pathway. In this study, we investigated the anti-hepatitis effects of two anti-inflammatory agents, ibudilast and dipyridamole, which are known to suppress LPS/TLR4-induced inflammation. In vitro antiviral activity was assessed in MHV68-infected 3T12 and MLE12 cells treated with ibudilast or dipyridamole (0-20 µg/ml). Viral replication was measured by quantitative PCR, and cell viability was assessed via water-soluble tetrazolium assay. In vivo efficacy was evaluated in MHV68-infected C57BL/6 mice treated with ibudilast, dipyridamole, the TLR4 antagonist C34, or vehicle. Hepatitis was assessed by monitoring body weight and serum AST/ALT levels. Dipyridamole significantly reduced MHV68 replication in vitro at 10 and 20 µg/ml without cytotoxicity. Ibudilast significantly reduced viral load; however, viral suppression was observed at cytotoxic concentrations. In vivo, both agents significantly reduced liver enzyme levels and mitigated body weight loss in infected mice. Their efficacy surpassed that of C34, a small-molecule TLR4 antagonist. Dipyridamole exhibited in vitro antiviral activity, and both agents effectively ameliorated MHV68-induced hepatitis in vivo. These findings highlight their therapeutic potential for acute hepatitis associated with extrahepatic viral infections, including EBV-associated disease.

Neutrophilic airway inflammation is associated with disease severity and exacerbation frequency in bronchiectasis. Neutrophil protease inhibition significantly reduced exacerbation rates in phase II and III trials in bronchiectasis, highlighting this disease feature as an important therapeutic target. Additional neutrophil targeting therapeutics are needed to reduce the burden of the disease. Herein, we describe the protocol for the AIR-NET trial, the first randomised, open-label, multifactorial, multicentre, adaptive platform trial for people with bronchiectasis, run via the EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) network, to investigate the safety and efficacy of several repurposed anti-inflammatory treatments.

Drug repurposing is an efficient strategy to accelerate the identification of therapeutic compounds by finding new uses for existing drugs. Here, we leveraged artificial intelligence (AI) to optimize this process and discover protein-protein interaction (PPI) modulators targeting the Neuronal Calcium Sensor 1. AI models were trained on large datasets of known PPIs, protein structures, and small molecular graphs to predict binding score. Using virtual screening of an FDA-approved drug library, the models generated a prioritized list of candidates. The most promising compounds were selected for experimental validation. This integrated approach efficiently reduced experimental workload, time, and cost, leading to the identification of dipyridamole as a selective modulator of the interaction between NCS-1 and the dopamine D2 receptor. The crystal structure of NCS-1 in complex with dipyridamole elucidates its mechanism of modulation. Our findings highlight the potential of AI to streamline and accelerate the discovery of novel therapeutic PPI modulators.