Safe and effective faxes offer hope for an end to the COVID-19 pandemic. However, the possible emergence of vaccine-resistant SARS-CoV-2 variants, such as new coronaviruses, makes treatments that work against all coronaviruses as important as ever. Now ACS researchers report ‘ Journal of Proteome Research have analyzed viral egg proteins across 27 coronavirus species and thousands of samples from COVID-19 patients, identifying highly conserved sequences that can produce the best drug targets.
Drugs often bind in “pockets” to egg whites that hold the medicine well, causing it to interfere with the function of the egg white. Scientists can identify potential drug-binding pathways from the 3D structures of viral proteins. Over time, however, viruses can mutate their egg whites so that medicines no longer fit. However, some drug-binding tubes are so essential for the function of the egg white that they cannot be mutated, and these sequences are generally preserved over time in the same and related viruses. Matthieu Schapira and colleagues wanted to find the highly conserved drug-binding pathways in viral proteins from COVID-19 patient problems and from other coronaviruses, making them the most promising targets for pan-coronavirus drugs.
The team used a computer algorithm to identify drug-binding tubes in the 3D structures of 15 SARS-CoV-2 proteins. The researchers then found similar proteins in 27 coronavirus species and compared their sequences in the drug-binding pockets. The two most conserved druggable sites were a pocket that overlapped the RNA binding site of helicase nsp13, and a binding pocket with the catalytic site of RNA-dependent RNA polymerase nsp12. Both of these proteins are involved in viral RNA replication and transcription. The drug-binding pocket on nsp13 was also highly conserved across thousands of SARS-CoV-2 samples taken from COVID-19 patients, with not a single mutation. The researchers say that new antiviral drugs targeting the catalytic side of nsp12 are currently in phase II and III clinical trials for COVID-19, and that the RNA binding site of nsp13 is a previously investigated target that a should be high priority for medicine development.
The authors recognize funding from the Natural Sciences and Engineering Research Council of Canada, the European Molecular Biology Laboratory and the Structural Genomics Consortium.
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