Novel host-specific molecule slows down SARS-CoV-2, influenza virus

Researchers in India have succeeded for the first time in synthesizing small molecules that can target the host and effectively block the infection of cells by SARS-CoV-2 and influenza viruses. The approach taken by the researchers is very different from the approach typically used to manufacture antiviral drugs. A team jointly led by researchers from IISER Mohali and IIT Ropar tried host-directed therapies as an alternative to antiviral drugs that directly target the virus in question. To date, there are no approved host-tropic drugs available against SARS-CoV-2 or influenza viruses.

A small molecule synthesized by Dr. Prabal Banerjee’s team in the IIT Ropar Department of Chemistry was shown to be more than 95% effective in blocking infection of cells by SARS-CoV-2 and influenza viruses in both cultured cells and animal studies . Result is, PLOS pathogen.

Antiviral drugs that target viruses become ineffective when the virus acquires resistance, but drugs that target host cells and prevent viral infection remain effective even if the virus accumulates mutations and evolves. expected to persist.

evidence

There is already evidence that currently FDA-approved drugs for treating SARS-CoV-2 and influenza virus infections are losing their effectiveness due to the emergence of drug-resistant virus strains. A challenge in host-directed therapy is that very often molecules can turn out to be toxic to the host cell, which is why this approach is not widely adopted.

This small molecule was not only effective (more than 95%) against both SARS-CoV-2 and influenza viruses, but was also non-toxic to both cultured cells and mice after long-term exposure.

“We first tested 28 compounds for their effectiveness in blocking influenza virus infection of lung cells. Of the 28 molecules screened, one molecule, the 1,3-diphenylurea derivative DPUD) was able to block both SARS-CoV-2 and influenza virus infection in cells by almost 100% without being toxic to the cells.” Prabal Banerjee is one of the corresponding authors. “This led us to synthesize 22 more DPUDs. One molecule tested against SARS-CoV-2 and two molecules tested against SARS-CoV-2 turned out to be highly effective without causing toxicity in animals.”

“The discovery of the host-tropic DPUD molecule was accidental,” says Nirmal Kumar, Ph.D. student at IISER Mohali and lead author of the paper. “When we started this study in early 2020, we were looking for potent anti-influenza drugs through high-throughput screening of small molecules. We identified a DPUD that effectively blocks influenza infection. After several experiments, we found that small molecules (DPUDs) are host-driven and that they block the cell entry pathway of influenza virus.”

During the COVID-19 pandemic, scientists have shown that SARS-CoV-2 uses the same pathway as the influenza virus to enter host cells.

“We hypothesized that because DPUD blocks common viral entry routes, it should also prevent SARS-CoV-2 infection. When tested, they were found to block infection almost completely: out of the 23 DPUDs we developed and tested, 5 showed very strong antiviral effects, and they were host-driven. It turns out there is,” says Kumar.

better recovery

“Compared to mornupiravir, the two DPUD molecules tested against SARS-CoV-2 in animals showed superior efficacy. It showed recovery and improvement in lung pathology,” said Indranil Banerjee of IISER’s Mohali Department of Biological Sciences, one of the paper’s corresponding authors. For influenza virus, one her DPUD was tested in mice.

“We mimicked the evolution of influenza viruses in the presence of Tamiflu and DPUD. The virus acquired resistance to Tamiflu after long-term exposure (10 generations), but not to DPUD tested. No,” says Dr. Indranil. “The virus remains susceptible to DPUD even after long-term exposure, which is why small molecules were able to inhibit infection.”

Dr. Indranil explained how the small molecule was able to block the virus from entering the cell, noting that chloride concentrations inside and outside the cell are different. Maintaining equilibrium in intracellular chloride concentrations is critical for endocytosis, the cellular process by which substances are brought into the cell.

“These molecules carry chloride ions into the cell, which causes large amounts of chloride to build up inside the cell, disrupting the chloride balance. When the chloride balance is disrupted, these viruses enter the cell.” Some of the endocytic pathways that it relies on for entry become dysfunctional, resulting in the virus being unable to enter cells and establish infection,” explains Dr. Indranir Banerjee.

However, the exact mechanism by which virus entry into cells is blocked by DPUD is not clear. The mechanisms by which nutrients enter cells even when the viral entry pathway is blocked need to be further investigated.

“Perhaps the small molecule targets the pathway the virus uses to enter the cell, leaving other pathways open, so cell health is unaffected,” Dr. Indranir says.

This small molecule was found to be highly effective when tested against H1N1 and H3N2 influenza virus subtypes and the concerned SARS-CoV-2 Wuhan, Delta, and two omicron variants .