BOS-318 / Boston Pharma - LARVOL DELTA

Furin Inhibition Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection. (PubMed, bioRxiv) - "This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection...Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections."

Journal • Preclinical • Acute Lung Injury • Bronchiectasis • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

BOS-318 treatment enhances elexacaftor-tezacaftor-ivacaftor-mediated improvements in airway hydration and mucociliary transport. (PubMed, ERJ Open Res) - "This altered ion transport profile effected an improved ASL height and MCT rate, which were significantly greater than improvements observed with ETI alone, demonstrating the benefits of the dual approach. Selective furin inhibition has the potential to further improve clinical outcomes for all people with CF and offers opportunity as an adjunct to improve responses to currently available CFTR modulator therapies."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

BOS-318 attenuates Pseudomonas aeruginosa lung infection in mouse models (NACFC 2024) - "Animals were anesthetized with isoflurane at the time of intraoral infection. BOS-318 decreased P. aeruginosa-induced lung injury and bacterial burden in mouse models. Our study introduces furin inhibition as a novel mechanism for anti-Pseudomonal therapy in animal models, protecting the lungs from injury and promoting bacterial clearance, which is highly applicable to CF lung disease and nosocomial pneumonia. Further research will target the mechanisms underlying this protective effect and extend to non-P."

Preclinical • Acute Lung Injury • Anesthesia • Cystic Fibrosis • Genetic Disorders • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • PTPRC

Furin Inhibition With BOS-318 Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection (ATS 2024) - "These data support furin inhibitor BOS-318 as a future therapy for Exo-A-induced lung injury and mortality in PA infection. Our study suggests BOS-318 decreases neutrophilic lung inflammation, and further research is ongoing to understand whether this pathway is mediated by platelets or other cytokines."

Late-breaking abstract • Preclinical • Acute Lung Injury • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • MIP-2 • TNFA

W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics. (PubMed, Comput Struct Biotechnol J) - "Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine "BOS" drugs (e.g., BOS-318) competitively inhibit human furin by an induced-fit mechanism in which tryptophan W254 in the furin catalytic cleft (FCC) functions as a molecular gate, rotating nearly 180 through a steep energy barrier about its chi-1 dihedral to an "open" orientation, exposing a buried (i.e., cryptic) hydrophobic pocket...Finally, interactive molecular dynamics (iMD) revealed two putative conduits of drug entry and binding into the FCC, each coupled with W254 dihedral rotation and opening of the cryptic pocket. The iMD simulations further revealed ligand entry and binding in the FCC is likely driven in part by energy fluxes stemming from disruption and re-formation of ligand and protein solvation shells during drug migration from the solution phase into the FCC."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Clearing the air: Uniquely engaging furin as an approach to cystic fibrosis therapy. (PubMed, Cell Chem Biol) - "describe a potent, specific, and cell-permeable furin inhibitor that interacts with a cryptic binding site to rescue hallmarks of cystic fibrosis in human ex vivo models. BOS-318 holds promise for development of therapeutics targeting an array of furin-dependent pathologies."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease. (PubMed, Cell Chem Biol) - "Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • ELANE