Since its first global appearance in 2012, Middle Eastern Respiratory Syndrome (MERS) has made its mark in 27 countries. Identified as an urgent threat by the World Health Organization, the virus replicates by deactivating a protein known as ubiquitin and kills on average about one-third of its victims. 

To date, scientists have been unable to develop a vaccine or treatment for MERS. However, a new study published in PLOS Pathogens describes a promising method of transforming ubiquitin into an antiviral drug that’s capable of stopping MERS in its tracks. 

MERS PLpro is a protease or enzyme the MERS virus encodes to elude human immune responses. It is essential for viral replication in human cells, Wei Zhang, PhD, a postdoctoral research fellow (Mitacs Elevate Fellow) with the Sidhu Lab at the University of Toronto and the study’s first author, told CLN Stat. 

Several small molecule inhibitors for MERS PLpro exist, but none of them have entered into clinical trials, “probably because of low potency and poor selectivity. This is due to the inherent structural complexity of this protein and similarity with human proteins in the same family,” Zhang explained. 

Investigators noted that ubiquitin, a small but stable protein, could bind to the active site of MERS PLpro.  

Viruses like MERS and Crimean-Congo hemorrhagic fever virus (CCHFV) “encode deubiquitinating enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon-stimulated gene 15 from cellular proteins to suppress host antiviral innate immune responses,” the investigators wrote. 

Zhang and his colleagues were able to re-engineer ubiquitin (a phage-displayed library of more than 10 billion ubiquitin variants, or UbVs) to develop a high-affinity UbV binder of MERS PLpro. “Since the UbV can occupy the active site of MERS PLpro with approximately 1,000-fold higher affinity than its natural interacting protein ubiquitin, in cells the enzymatic function of MERS PLpro is blocked,” Zhang said. 

Through this method, the investigators were able to eliminate the MERS virus in a dish within a day and had similar success with CCHFV. “We showed that expression of a UbV in MRC5 and HuH-7 cells during MERS coronavirus infection reduced infectious progeny titers by more than four orders of magnitude,” Zhang added. 

For future research, the investigators plan to develop protein delivery methods for UbV in human cells and animal models, and conduct small molecule displacement screens to find UbV-mimetic compounds, Zhang said. 

“We want to screen for small molecules that can function as our UbV inhibitors, as those molecules can be relatively easily delivered and commercialized,” he explained.