The papain-like protease (PLpro) of SARS-CoV-2 plays an essential role in the processing of viral proteins necessary for replication. In addition, the enzyme can cut and inactivate certain human proteins important for an immune response. Now, researchers reporting in Infectious diseases of ACS found other targets of PLpro in the human proteome, including proteins involved in cardiovascular function, blood clotting and inflammation, suggesting a link between inactivation of these proteins and symptoms of COVID-19.
Viruses like SARS-CoV-2 make several proteins in the form of a long “polyprotein”. Viral enzymes called proteases recognize specific amino acid sequences in this polyprotein and cut them to release individual proteins. However, some human proteins also contain these sequences (called homologous host-pathogen sequences, or SSHHPS), including those involved in the generation of the innate immune response, which could help protect the virus from the host. Patricia Legler and her colleagues wanted to comprehensively identify human proteins containing SSHHPS, examine their functions, and see if PLpro can cleave them in a test tube.
Researchers have developed a computational method to search a database of all known human proteins for sequences similar or identical to those of SARS-CoV-2 SSHHPS. Analysis revealed that the proteins with the highest sequence identity were those that had cardiovascular, inflammatory, renal, respiratory, or blood-related functions. For example, two of the proteins containing SSHHPS were cardiac myosins, one was an anticoagulant, and another was an anti-inflammatory protein. Inactivation of these proteins by PLpro is consistent with COVID-19 symptoms of heart damage, blood clots, and inflammation. The team confirmed that PLpro could cut these protein sequences in vitro. Performing the same analysis on SSHHPS for the Zika viral protease identified proteins associated with development and neurological disorders, consistent with the symptoms of Zika. These results suggest that the symptoms and virulence of viruses can be predicted directly from their genomic sequences, the researchers say.
The authors acknowledge funding for the Office of the Secretary of the Navy, funding for Innovative Naval Science and Engineering, and the Office of Naval Research.
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