Progress toward antiviral treatments for COVID-19

COVID-19 is caused by a virus known as SARS-CoV-2, which is similar in structure to two other viruses that have caused recent outbreaks: SARS-CoV, which caused an outbreak of SARS in 2003, and MERS-CoV, the cause of a 2012 outbreak of Middle East Respiratory Syndrome.

In The Journal of Chemical Physics, by AIP Publishing, scientists from the University of Maryland School of Pharmacy report molecular-level investigations of these three viruses, providing a possible pathway to new antiviral drugs to fight all three diseases. At the present time, no effective treatment or drugs exist for any of these coronavirus diseases.

The investigators looked at a viral protein that plays a key role in the ability of the virus to replicate itself once inside the body. This protein also plays a role in defeating the host's immune system, so it provides a particularly attractive target for potential drug treatments.

The protein, an enzyme known as the papainlike protease, PLPro, is nearly identical in SARS-CoV-2 and SARS-CoV but is slightly different in MERS-CoV. Very recently, the first structural X-ray of this enzyme revealed a shape in the catalytic domain somewhat like a hand with a "thumb," "palm," and "fingers."

The thumb and palm come together to form a binding site, where a drug molecule could potentially be captured. The fingers fold down over this region and provide structural integrity that is essential for PLPro activity.

The investigators discovered small shifts in pH could change the shape of this enzyme through a process known as protonation, where hydrogen ions bind to certain amino acid units in the protein.

"Protonation state switch is an important energy transduction mechanism," said author Jana Shen.

Co-author Jack Henderson said, "The coronavirus spike protein, for example, makes use of protonation state switches to induce large conformational changes required for membrane fusion."

Membrane fusion is the first step in infection. A virus attaches to the outer membrane of a cell, making its way inside where it can begin to form copies of itself that spread throughout the body.

Another key feature of the PLpro binding site is a string of amino acid units called the BL2 loop. The investigators found this loop can open or close in SARS viruses when a particular amino acid on the loop is either protonated or deprotonated. In the MERS virus, however, the loop is flexible even without such an amino acid.

This feature suggests a potential drug could target the BL2 loop, causing it to close and tightly bind to a viral inhibitor.

"Our work provides a starting point for further mechanistic investigations using higher-level approaches," said Shen.

Jack A Henderson, Neha Verma, Robert C Harris, Ruibin Liu, and Jana Shen.
Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors.
J. Chem. Phys. 153, 115101, 2020. doi: 10.1063/5.0020458

Most Popular Now

Observational study identifies drug that improves …

Researchers at Hackensack Meridian Health, New Jersey's largest and most comprehensive health network, have utilized its statewide observational database of more than 5,0...

73,000 Scientists collaborate over new COVID-19 Da…

More than 73,000 users collaborate on new online platform set up by the European Open Science Cloud Initiative, where scientists share COVID-19 data and accelerate our un...

Antiviral used to treat cat coronavirus also works…

Researchers at the University of Alberta are preparing to launch clinical trials of a drug used to cure a deadly disease caused by a coronavirus in cats that they expect ...

Roche and Regeneron collaborate to significantly i…

Roche (SIX: RO, ROG; OTCQX: RHHBY) and Regeneron (NASDAQ: REGN) announced are joining forces in the fight against COVID-19 to develop, manufacture and distribute REGN-COV...

Search for COVID-19 drugs boosted by SARS discover…

An extensive search and testing of current drugs and drug-like compounds has revealed compounds previously developed to fight SARS might also work against COVID-19. Us...

Pfizer and BioNTech share positive early data on l…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) shared additional Phase 1 safety and immunogenicity data from their ongoing U.S. study of the BNT162 mRNA-based vac...

Phase I clinical trial initiated for monoclonal an…

The first participants have been dosed in a Phase I trial of AZD7442, a combination of two monoclonal antibodies (mAbs) in development for the prevention and treatment of...

Europe's largest initiative launches to accelerate…

CARE (Corona Accelerated R&D in Europe) a new consortium supported by the Innovative Medicines Initiative (IMI) public-private partnership announced its launch to acceler...

Vitamin D deficiency may raise risk of getting COV…

In a retrospective study of patients tested for COVID-19, researchers at the University of Chicago Medicine found an association between vitamin D deficiency and the like...

Blocking cellular communication stops SARS-CoV-2

In the transmission of signals within the cell which, for example, stimulate cell growth or trigger metabolic processes, phosphate groups play an important biochemical ro...

Improving FDA's COVID-19 vaccine authorization and…

On March 28, the Food and Drug Administration (FDA) exercised its Emergency Use Authorization (EUA) authority to allow the use of hydroxychloroquine for the treatment of ...

Steroid found to improve survival of critically il…

A new international study published today has shown that treating critically ill patients with COVID-19 with the steroid hydrocortisone improves their chances of recovery...