Molecular Mechanisms of Poxvirus Proteases I7 and G1

The Poxviridae comprise a family of complex cytoplasmic replicating DNA viruses that includes a number of important human and animal pathogens such as Variola virus, the causative agent of smallpox, Monkeypox virus, Cowpox virus and Vaccinia virus. Despite the successfully eradication of smallpox as a human disease by the worldwide vaccination campaigns 30 years ago, there nowadays still remains a considerable fear that Variola virus could be used as a bioweapon. Additionally, the re-emergence of zoonotic poxviruses such as the human Monkeypox virus outbreak that occurred in 2003 in the United States, Cowpox virus outbreaks in Europe and Vaccinia virus outbreaks in Brazil and India in the last years renewed the interest in the search for new anti- poxviral drugs. Besides, there is only one antiviral agent currently approved by FDA (Food and Drug Administration) for use against orthopoxviruses: cidofovir. However there are some concerns about its use, since cidofovir therapy can lead to renal and ocular toxicity, and also because cidofovir-resistant strains of camelpox, cowpox, monkeypox and vaccinia viruses have been isolated. In this context, the two poxvirus proteases, I7 and G1, arise as interesting protein targets for anti-poxvirus drugs development. In fact, it was previously showed that both I7 and G1 proteolysis activity are essential for viral replication and that these proteins have low identity with cellular proteins. These facts highlighted them as attractive antiviral targets. However, much essential knowledge of the molecular mechanisms of both proteases remains unexplored. This project aims to investigate more deeply both the structure and the function of these proteases. Indeed, the first structure of a poxvirus protease can be expected as well as the first insights about G1 substrates which imply an increase of knowledge about its role on Poxvirus multiplication cycle. We thus believe that this research will generate molecular and structural data essential not only to anti-poxviral drug design but also for the better understanding of the complex poxvirus life-cycle. In particular for the host institute, this research proposal would mean the introduction of Poxviridae family of virus as an object of further studies.