A group of researchers has worked with human coronaviruses in cell cultures to look for drugs that might prevent accumulation and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thiopurines activate an antiviral unfolded protein response that is said to block the viral glycoprotein buildup in the cell culture infection model. The researchers explicated that viruses that are enveloped, such as the coronavirus, have genetic material that can code for membrane proteins that can be synthesized and modified in the endoplasmic reticulum (ER) before they can be transported to the areas of assembly of the parts of the virion.
An overload of virion particles may lead to an overwhelmed ER protein folding which leads to unfolded proteins in the ER. This triggers an unfolded protein response (UPR). Their fast replication is involved when the virus particle invades a cell which burdens the ER. The virus discharges a burst of glycoproteins that overwhelms the ER. However, the virus is capable of bypassing the UPR and promotes efficient replication. Several coronaviruses are said to activate UPR. This includes the infectious bronchitis virus (IBV), mouse hepatitis virus (MHV), transmissible gastroenteritis virus (TGEV), human coronavirus (HCoV)-OC43, and SARS-CoV-1. The team recognized two FDA-approved thiopurine analogs called 6- thioguanine (6-TG) and 6-thioguanosine (6-TGo) which could block IAV and HCoV-OC43 replication when their dose was increased in a graded manner.
Pateamine A and Silvestrol had been tested previously. These two thiopurines were found to disturb the process of growth of viral glycoproteins that could activate the UPR. In the 6-TG treated cells, the viral glycoprotein synthesis could be partly restored by the chemical inhibition of the UPR. The CoV Spike (S) proteins expressed on the surface of the virus presented UPR activation. The data discloses that the UPR-inducing molecules could act as effective host-targeted antivirals against viruses that depend on ER processes to support efficient replication. The induction of UPR by 6-TG and 6-TGo could be a novel technique through which an antiviral mechanism could be triggered by the host cell itself. This has been a previously unrecognized unique mechanism of action, they said.
Ref link: https://www.biorxiv.org/content/10.1101/2020.09.30.319863v1