Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.

Frontrunners in the race to develop a SARS-CoV-2 vaccine.

Numerous studies continue to be published on the COVID-19 pandemic that is being caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Given the rapidly evolving global response to SARS-CoV-2, here we primarily review the leading COVID-19 vaccine strategies that are currently in Phase III clinical trials. Nonreplicating viral vector strategies, inactivated virus, recombinant protein subunit vaccines, and nucleic acid vaccine platforms are all being pursued in an effort to combat the infection. Preclinical and clinal trial results of these efforts are examined as well as the characteristics of each vaccine strategy from the humoral and cellular immune responses they stimulate, effects of any adjuvants used, and the potential risks associated with immunization such as antibody-dependent enhancement. A number of promising advancements have been made toward the development of multiple vaccine candidates. Preliminary data now emerging from phase III clinical trials show encouraging results for the protective efficacy and safety of at least 3 frontrunning candidates. There is hope that one or more will emerge as potent weapons to protect against SARS-CoV-2.