Inhibitor against influenza
Broad-spectrum influenza treatment and other respiratory-related viruses, idiopathic pulmonary fibrosis (IPF) and osteoarthritis (OA)
Potent and selective inhibitors of matriptase, lung surface Type II transmembrane serine proteases (TTSPs), implicated in a number of pathophysiological processes including influenza viral replication, osteoarthritis, idiopathic pulmonary fibrosis, cancer, wound healing, cystic fibrosis and inflammatory skin disorders.
Reversible covalent binding to the catalytic site of matriptase.
Since these compounds are designed to inhibit multiple TTSPs, broad-spectrum anti-influenza activity is expected and is supported by preclinical data.
Influenza and other respiratory-related viruses: The influenza virus critically relies on the host to cleave and activate its hemagglutinin (HA) fusion protein to replicate and enter into the lung epithelium. Since the virus does not encode for any protease, host proteases are critically required to cleave HA.
Recent studies show that certain TTSPs are capable of initiating HA cleavage to enable viral infection in human lung epithelial cells. The extracellular location of these proteases in airway epithelial cells, and the observation that human influenza A HAs possess a single arginine (Arg) residue at the HA cleavage site, make this a particularly attractive therapeutic target for inhibitor design.
Inhibition of matriptase by our slow tight‐binding inhibitors significantly block influenza replication in human bronchial epithelial cells and in mice when delivered intranasally.
Preliminary safety studies in mice with inhibitors have not identified any significant safety issues related to the enzyme inhibition. In vitro, after over 12 passages, there has not been any development of resistance to our inhibitors, whereas, under a similar protocol, resistance to Tamiflu® develops after four to five passages.
Based on the rationale and evidence for influenza, matriptase inhibitors can also prevent coronavirus infections.
IPF : The serine protease matriptase plays a driving role in the development of IPF, via activation of PAR-2 receptors.
OA : Matriptase is expressed in chondrocytes of human OA cartilage, where it enhances collagenolysis via PAR-2 and matrix metalloproteases, both key players in OA. Reduction of OA severity in a mouse model of OA has been observed with i.a administration of matriptase inhibitors.