Abstract
Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CLpro) which processes the 200 kDa viral polyprotein into six functional proteins. The 3CLpro has attracted much interest due to its potential as a target for antiviral drugs. A system for growing high-quality crystals of native Southampton norovirus 3CLpro (SV3CP) has been established, allowing the ligand-free crystal structure to be determined to 1.3 Å in a tetrameric state. This also allowed crystal-based fragment screening to be performed with various compound libraries, ultimately to guide drug discovery for SV3CP. A total of 19 fragments were found to bind to the protease out of the 844 which were screened. Two of the hits were located at the active site of SV3CP and showed good inhibitory activity in kinetic assays. Another 5 were found at the enzyme’s putative RNA-binding site and a further 11 were located in the symmetric central cavity of the tetramer.
Highlights
Gastroenteritis accounts for the deaths of over 2000 children every day worldwide, making it the second leading cause of death for children under the age of 5, more than the combination of AIDS, malaria and measles (Liu et al, 2012)
It is clear that the backbone of this β-hairpin moves by over 7 Å to open up the active site cleft for substrate binding and movements of some of the side chain atoms exceed of 12 Å
The X-ray structure of the Southampton virus 3C-like cysteine protease (3CLpro) has been determined at 1.3 Å resolution in a crystal form that has allowed fragment-screening for novel inhibitors to be undertaken at similar resolutions
Summary
Gastroenteritis accounts for the deaths of over 2000 children every day worldwide, making it the second leading cause of death for children under the age of 5, more than the combination of AIDS, malaria and measles (Liu et al, 2012). Whilst there are many other causes of gastroenteritis, including parasites, bacteria and viruses, human caliciviruses are recognised as the leading cause of gastroenteritis worldwide among people of all ages. Noroviruses account for more than 50% of gastroenteritis cases and at least 90% of nonbacterial acute gastroenteritis cases worldwide, as reported by the Centers for Disease Control and Prevention in the US (2011). It is estimated that noroviruses lead to a total of $4.2 billion in direct health system costs and $60.3 billion in social cost per year (Bartsch et al, 2016)
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