Inhibitor Candidates to Stop SARS-CoV-2 Replication Process Examined: Study
Thu, April 22, 2021

Inhibitor Candidates to Stop SARS-CoV-2 Replication Process Examined: Study



A group of researchers is working on the molecular motors of SARS-CoV-2. In this research, they explored which inhibitor candidates that would not be mitigated by mutations.

The potency of inhibitor candidates for the SARS-CoV-2's targeted helicase was investigated by Rockefeller University, a private university in the US. Researchers found that the helicase could be inhibited to prevent the virus from replicating. However, mutations could fix the effects of an inhibitor. As such, they used a computational method to predict inhibitor candidates less likely to be affected by changes. The computational method has been used in cancer drug discovery.


Helicases for Viral Replication

When a virus infects a host cell, it hijacks the cellular machinery to replicate more copies and infect more cells. The viral replication process involves the utilization of a suite of enzymes and proteins, which the cell uses normally. This suite copies the genetic material of the virus to produce thousands of copies. After some time, the new copies will burst out of the infected cell and seek healthy ones to repeat the process.

SARS-CoV-2, the virus of COVID-19, follows that replication process by taking over the molecular motors in cells called helicases. While the majority of scientists around the world are focused on treatments and vaccines, some are in search of ways to stop the replication process. At Rockefeller University, the helicase is the essential item the coronavirus requires.

"If you think of the helicase as a machine with many different parts, we are trying to find molecules that can stick to one of the parts and disrupt the machine," said Tarun Kapoor, a professor at Rockefeller and researcher involved in COVID-19 projects.

Kapoor's lab has been studying different drugs and other substances that can inhibit the growth of malignant cells. His team discovered some compounds capable of inhibiting enzymes in cancer cells. These compounds are refined to create therapeutic drugs to help cancer patients. But COVID-19 happened and their research may give insights into the coronavirus' replication.



Researchers shifted their attention to SARS-CoV-2 and adapted their anticancer strategy to COVID-19. Lab analyses unveiled helicases being manipulated by the virus. Helicases could be found in living organisms as they are needed for DNA-related instructions. If hijacked by SARS-CoV-2, helicases would unzip the viral RNA to prepare the replication process. Thus, subduing a specific enzyme in the helicases could disrupt the process.

After various experiments, they identified the enzyme associated with the virus: the NSP13. This was unveiled with the help of genome sequences made available since January 2020. Details of the enzyme unveiled its molecule composition. Researchers used those details to find potential inhibitors in large libraries of chemical compounds. The libraries gave them compounds with the capabilities of restraining that enzyme.

But the team did not stop there. Since viruses could mutate over time, they implemented a computation model called resistance analysis during design (RADD). This has been used for cancer drug discovery to highlight cancer cell mutations, which could render anticancer drugs useless. They applied it for inhibitor candidates of NSP13 to measure potency during viral mutations. One of the compounds was detected with the highest potency against SARS-CoV-2 and zero toxicity to host cells.

Right now, the research team is working on converting those compounds into medications. But it will take several months before the compounds can be approved for therapeutic purposes. They hope by that time a COVID-19 vaccine is already in circulation. The drugs will serve as an augmentation to the vaccine and possible therapy for those who will not respond to immunization.



Phase III Clinical Trial of mRNA-1273 Vaccine

According to the National Institutes of Health, a US agency, the experimental vaccine mRNA-1273 has started its Phase III clinical trial. The trial will evaluate if the vaccine can prevent the symptoms of COVID-19 among adults. The trial's cohort size is about 30,000 healthy adults. Previous clinical trials suggested that the vaccine is safe and immunogenic or can induce an immune response.

In The New England Journal of Medicine, the preliminary report of Phase I trial presented the potential of mRNA-1273. The vaccine used a part of the SARS-CoV-2 to trigger an immune response. It is opposed to the MMR vaccine design, in which inactivated pathogens were used. Phase I trial included 45 healthy adults aged 18 to 55 years. All participants received two shots of the experimental vaccine with an interval of 29 days between shots. The doses were 25 micrograms, 100 micrograms, and 250 micrograms of mRNA-1273.

Each dose group had 15 participants and were observed for immune responses and side effects. Observations showed that higher doses yielded higher antibody responses. The average quantitative values of immune responses from the first vaccination were 40,227 in the 25-microgram group, 109,209 in the 100-microgram group, and 213,526 in the 250-microgram group. After the second vaccination, the values increased to 299,751 in the 25-microgram group, 782,719 in the 100-microgram group, and 1,192,154 in the 250-microgram group.

In terms of adverse events, participants reported several side effects including fatigue, chills, headache, myalgia, and pain at the injection site. More than 50% of participants reported those side effects. Severe side effects were more common after receiving the second dose, especially among participants in higher dose groups. About 21% of those in the 250-microgram group reported one or more severe side effects.

The authors concluded that the 100-microgram dose of mRNA-1273 is the most optimal of all three doses. It could induce sufficient antibody response at a lower risk of adverse effects, compared to the 25-microgram and 250-microgram doses. The findings supported the Phase II trial that involved 600 healthy adults, who were given either 50 micrograms or 100 micrograms of the vaccine.

The Phase III trial will evaluate the effects of the experimental vaccine in the 100-microgram dose. Participants will be assigned randomly to receive either the vaccine or placebo. Two shots will be administered with an interval of 28 days between shots.