A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

CoVaRR-Net experts have used computers to strategically design a new drug called C5a, which offers an alternative treatment to Paxlovid for COVID-19. There is evidence that C5a will remain resilient to changes in the SARS-CoV-2 virus that may make it effective against future emerging coronaviruses, whereas there is a chance that Paxlovid will cease being effective with further virus mutations. In addition, C5a targets a viral protein that has already been demonstrated to be effective against COVID-19 and that causes limited side effects.

This discovery was led by Dr. François Jean, CoVaRR-Net’s Antiviral Strategies & Antiviral Therapeutics (Pillar 10) Lead, and his colleagues, including Dr. Natalie Strynadka (CoVaRR-Net Pillar 10 Deputy and Professor, Biochemistry and Molecular Biology, University of British Columbia (UBC)) and Dr. Artem Cherkasov (Professor, Faculty of Medicine, UBC). The research was done using funding provided in part by CoVaRR-Net.

“I believe we are close to seeing SARS-CoV-2 mutate enough that it will evade all remaining treatments,” said Dr. François Jean, Associate Professor of Virology at the University of British Columbia. “Our next-generation antivirals in development, such as C5/C5a, have the potential to fill significant treatment gaps in the short term associated with BA.2 variants such as BA.2.86 and to ensure future, long-term preparedness.”

Treatments that slow or stop SARS-CoV-2 from spreading inside infected individuals have become an important tool for limiting the harmful effects of COVID-19. In Canada, two drugs are approved for people with mild to moderate symptoms that are at higher risk of serious illness: Paxlovid (nirmatrelvir/ritonavir) and Remdesivir (Veklury). These treatments help prevent symptoms from getting worse and work best when given to people shortly after their symptoms start. Treatment with Paxlovid during the early stages of COVID-19 may also reduce the risk of developing post-COVID complications (such as Long COVID).

Both drugs target a virus-specific protein called 3CLpro (pro is short for protease, which is a protein that cuts and activates other virus proteins needed for infection). C5a is as effective as Paxlovid at blocking the highly pathogenic Delta SARS-CoV-2 variant, as well as highly transmissible Omicron variants including BA.2, BA.5, BQ1.1 and XBB.1.5. Because SARS-CoV-2 continues to evolve faster than new drugs and vaccines can be made, it is important that any new treatments for COVID-19 are able to withstand a wide array of changes in the virus. C5a was also shown to work against a more distant relative of SARS-CoV-2 called coronavirus 229E, which can cause the common cold. This is further evidence that C5a will remain resilient to changes that continue to occur in SARS-CoV-2 and that it may also be effective against future emerging coronaviruses.

Several samples of SARS-CoV-2 virus taken from infected people in Canada have been found to contain mutations that may stop Paxlovid from working. If these mutations become widespread, the usefulness of Paxlovid could be lost. C5a targets a different part of 3CLpro than Paxlovid. Based on experiments done to understand the physical interaction between 3CLpro and C5a, the study team found that C5a should still interact with 3CLpro in the presence of mutations that would limit the effectiveness of Paxlovid.

The key advantage of C5a is that it targets a viral protein that has already been demonstrated to be effective against COVID-19 and that causes limited side effects. Consistent with this, Dr. Jean’s team found a favourable safety profile of C5a in lung and colon cells. Two other promising drugs identified by his team include N-0385, which targets a human protein needed by the virus to get into people’s cells, and Bafilomycin D, which targets another human protein used by the virus to spread once it gets inside cells. In this study, Dr. Jean’s team has shown that C5a acts synergistically when used in combination with either N-0385 or Bafilomycin D. This means both drugs work better when used with C5a than when used alone, and lower amounts of drug would be needed for treatment. Treatments that combine multiple drugs also make it more difficult for the virus to escape the treatment through mutations.

Read article