COVID-19 Inhibition by Novel Glycan Therapy PRM-A

HIV, Ebola, and, most recently, COVID-19 viruses have had far-reaching consequences for our civilizations around the world. All of these viruses are ‘enveloped viruses,’ meaning they have an external envelope made up primarily of cells from their host. This envelope enhances the virus’s capacity to hide from the host’s immune system and enter the host’s cells. It also provides researchers with a target, or a chance, to disrupt viral transmission.

Japanese researchers have been researching on preventing viral transmission in these sorts of viruses.

The development of vaccines and antiviral drugs against COVID-19 has successfully reduced the risk of death, but complete suppression of viral transmission is still challenging. Under such circumstances, we evaluated the potential of naturally occurring pradimicin A (PRM-A) as a new anti-SARS-CoV-2 drug that suppresses SARS-CoV-2 (COVID-19) transmission.”

Yu Nakagawa, lead author on the paper and associate professor in the Institute for Glyco-core Research (iGCORE) at Nagoya University, Nagoya, Japan

There is significant evidence that PRM-A is a viral entry inhibitor, which means it prevents viruses from entering a host’s cells. It does this by binding to N-glycans, which are found on the surface of several types of enveloped viruses including the SARS-CoV-2 virus. However, very little is known about how PRM-A binds to viral N-glycans.

To infect a cell, a virus’s envelope uses specific receptors on its surface called spike proteins, which are usually glycoproteins, meaning carbohydrates, specifically sugar (oligosaccharides) attached to proteins, to bind to the cellular membrane of a host cell, causing a conformational change in the cell membrane that allows the virus to enter the cell. Once there, it exploits the cell’s resources to copy its own DNA, avoiding the host’s immune system.

Initially, researchers attempting to disrupt viral transmission concentrated on lectins, carbohydrate-binding proteins originating from plants or bacteria, which showed great promise as a viral entry inhibitor. They bind to the virus’s glycoproteins, halting its progression into a cell. However, they are frequently pricey, easily targeted by the host’s immune system, and can be poisonous to the host’s cells. Lectin mimics offer many of the same carbohydrate-binding properties as lectins but without the pricey and harmful side effects.

The Japanese researchers examined PRM-A, a naturally occurring lectin mimic. It has showed promise as a viral entrance inhibitor, with evidence that it binds to the N-glycans of the virus’s envelope glycoproteins. To determine the molecular basis of the interaction, they employed molecular modeling and binding experiments to analyze the reactions between PRM-A and N-glycans as they bind. They also conducted in vitro tests to determine PRM-A’s ability to suppress SARS-CoV-2 (COVID-19).

They discovered that PRM-A specifically binds to branched oligomannose structures observed in viral spike proteins with high mannose-type and hybrid-type N-glycans. Mannose is the particular sugar present in these N-glycans. They also discovered that PRM-A reduced the infectivity of SARS-CoV-2. In fact, the inhibition was caused by the interaction of PRM-A and branched oligomannose-containing N-glycans.

“We demonstrated for the first time that PRM-A can inhibit SARS-CoV-2 infection by binding to viral glycans. It is also noteworthy that PRM-A was found to bind preferentially to branched oligomannose motifs of viral glycans via simultaneous recognition of two terminal mannose residues. This finding provides essential information needed to understand the antiviral mechanism of PRM-A,” said Nakagawa.

Nakagawa and their team are already busy working on the next step in their research. “Our ultimate goal is to develop anti-SARS-CoV-2 drugs based on PRM-A. The glycan-targeted antiviral action of PRM-A has never been observed in major classes of the existing chemotherapeutics, underscoring its potential as a promising lead for antiviral drugs with the novel mode of action. Especially, considering that glycan structures are hardly changed by viral mutation, we expect that PRM-A-based antiviral drugs would be effective against mutated viruses. Toward this goal, we are now examining in vivo antiviral activity of PRM-A using hamsters, and also developing PRM-A derivatives that are more suitable for therapeutic applications,” said Nakagawa.

For more information: Nakagawa, Y., et al. (2024). Molecular basis of N-glycan recognition by pradimicin a and its potential as a SARS-CoV-2 entry inhibitor. Bioorganic & Medicinal Chemistry. doi.org/10.1016/j.bmc.2024.117732.