Updated: Dec 29, 2020
A remarkable discovery during COVID-19 studies is the ability of GRL-0617 a PLpro inhibitor to block SARS-CoV-2 production in cell cultures, leading to possible improvement in the cell’s immune response.
This finding was uncovered while monitoring the mechanism of infection of cells by SARS-CoV-2 virus. This led to the discovery of papain-like protease (PLpro) inhibitors.
The conception is that, in the case of COVID-19 infection, SARS-CoV-2 must first overcome the host’s cells defence mechanisms; both innate and adaptive immune systems. During this process, type 1 interferons are released by infected body cells to recruit immune cells such as natutal killer cells, to the infected site.
The innate or non-specific immune response is somewhat suppressed by SARS-CoV-2, this is one of the major exceptionalities of the virus that makes its infection process successful. More so, it allows the production of papain-like-protease (PLpro) by the infected human cell. The functions of PLpro include, maturation and release of new viral particles and suppression of the development of type 1 interferons.
During the study, it was found that, blocking PLpro, the production of the virus was inhibited thus strengthening the innate immune response of the infected human cells.
Following thorough analysis of the GRL-0617, a non-covalent inhibitor of PLpro, for its mode of action very closely in terms of biochemistry, structure and function, it was concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. clinical trials on PLpro-inhibiting substance classes for use in is now a key challenge for this therapeutic approach.
It was also noted that PLpro is capable of cleaving interferon-stimulated gene 15(ISG-15) from cellular proteins with a higher level of activity than the severe acute respiratory syndrome (SARS) equivalent, leading to greater inhibition of type I interferon production. This is in accordance to recent clinical findings that demonstrate SARS-CoV-2, reduction of in terferon response in comparison to other respiratory viruses such as influenza and SARS.
This findings make PLpro an extremely attractive antiviral target because its inhibition would be a “double strike” against SARS-CoV-2, preventing viral replication and strengthening the human immune response.