Intervention of viral infections by targeting host cellular protease : A proposition based on viral glycoprotein processing

摘要

During the past century our world has witnessed a number of global pandemic outbreaks of viral infections from time to time, often with deadly consequences. However, in recent years viral infections of new types or variants are beginning to emerge often with significantly high virulence properties. A number of these new strains are derived from animals such as avian, cattle, primates, etc. which have crossed the animal barrier due to varying reasons that may include the change in lifestyle, food habit, increased migration, globalization as well as living and staying too close to animals. Extensive research has been undertaken to better understand the genetic and protein architectures of these and other highly infectious viruses and their mode of progression. Already potential targets have been identified for development of safe and effective intervention and treatment strategies. These are all directed towards the viral components such as viral enzyme, viral protein and viral membrane associated with the fusiogenic event. However, host cellular enzytnc/s of protease family also plays a critical role in viral pathogenesis and infection. It cleaves viral surface glycoproteins leading to their maturation forms to be recognized by host cellular receptor. This leads to viral fusion with host membrane and delivery of its components leading to viral replication and progression. As a result, these selected host proteases may also be considered as important targets for blockade of viral infection and pathogenesis. In this respect, one enzyme in particular called furin (also known as PCSK3) that belongs to the Proprotein Convertase Subtilisin Kexin (PCSK) super family stands out the most. In fact, furin inhibitors have been developed and shown in vitro and animal models to diminish viral replication and its load. Development of highly selective furin inhibitors is thus an attractive option to fight against the viral infections despite the challenge one has to face in terms of enzyme specificity, potency and delivery of anti-furin agents in an organ/tissue-specific manner. This review discusses the various issues facing this approach. Both pros and cons of this methodology are discussed and debated in this review.