Abstract
US researchers have found that inhibitors of cathepsin L enzyme prevent severe acute respiratory syndrome (SARS) virus from entering target cells.
Keywords: inhibitors, binding, receptor, vesicle, protease
US researchers have found that inhibitors of the cathepsin L enzyme prevent severe acute respiratory syndrome (SARS) virus from entering target cells. ‘This study demonstrates a new mechanism for how viral proteins are activated within host cells’, said Paul Bates, Associate Professor in the Department of Microbiology in the University of Pennsylvania's School of Medicine (PA, USA). ‘This paper changes the thinking of the field’, said Bates about the findings published in the early August issue of Proceedings of the National Academy of Sciences. ‘Everyone thought all of the activation steps were at the cell surface or due to the low pH environment in the vesicle. Our paper shows that it is not just low pH but the cathepsin proteases in the vesicles that clip the viral protein. This gives us a new target to address in the development of therapeutics against the SARS virus’.
‘…a new target to address in the development of therapeutics against the SARS virus.’
The role of cathepsins in SARS virus infection
A typical virus gains entry into a cell by binding to the receptors on the surface of the cell itself and it is taken up into a vesicle inside the cell. However, SARS virus needs one more step to infect the cell. Proteins within the membrane of SARS virus particles need to be cut by the cathepsin enzymes before they replicate within the host cell.
Cathepsins act in the low-pH environment inside the vesicle and this causes the viral membrane to fuse with the vesicle membrane, thus, viral proteins and nucleic acids can enter the cell (where viral replication occurs). The researchers found that several chemical inhibitors of cathepsin activity blocked the infection of human cell lines by the SARS virus. This research was conducted in a high-level-safety laboratory. These findings have led to a better understanding that the cutting of viral protein by cathepsins is necessary for viral infection and is probably not unique because both the SARS and Ebola viruses are now known to use a similar mechanism to invade their host cells.
Cytotoxic problems and extracellular protease involvement
‘There is growing interest in cathepsins as mediators of viral entry’, said Sue Delos (Professor of Research in Cell Biology from the University of Virginia, USA). ‘In fact a role for cathepsins in reovirus and Ebola has been documented previously’, she told Drug Discovery Today. Although Delos called the study ‘thorough and convincing’, she identified two problems with targeting cathepsins for inhibition. First, cathepsins are important for normal cellular function and second, extracellular proteases could also function in viral entry (extracellular protease-mediated entry, particularly at the sites of initial infection). ‘Thus, cathepsin inhibition may be insufficient to prevent SARS infections’, said Delos. ‘Clearly, post-maturation proteolysis is required to activate each of these viruses. Targeting the proteolytic sites in the viral glycoproteins may provide more specific inhibition. Many labs are currently working to identify these sites’.
Polly Roy (Professor of Virology, at the London School of Hygiene & Tropical Medicine, UK) also had some reservations. She said the significance of the study for developing antivirals might be limited because cathepsin L was not SARS-CoV specific. ‘Thus any inhibitor of this protease may disrupt other pathways associated with normal cellular processes and could be cytotoxic’, said Roy. ‘This work is of course very significant as cleavage of the SARS-CoV fusion protein does not occur during normal maturation of the protein. No doubt this will open up a new direction of research in the understanding of molecular events, not only in SARS-CoV virus entry mechanism but possibly for other enveloped viruses’.
Conclusions
SARS, caused by an emergent coronavirus, is a respiratory disease of unknown etiology that originated in mainland China in 2003. It is characterized by fever and coughing, difficulty breathing or hypoxia and it can be fatal. More than 8000 people were infected and 750 people were killed when the disease swept the world in 2003 forcing WHO to issue an unprecedented world-wide alert.
Currently there is no effective treatment although patients have been given steroids in an attempt to help their lungs cope with the infection. Peter Openshaw, a professor from the National Heart and Lung Institute at Imperial College London, UK, told Drug Discovery Today that ‘a drug that works generically for CoVs would be a big step forward… But this is all in vitro and many drugs fall at the in vivo transition stage’.