Promising anti-cancer drug also may function as COVID-19 antiviral therapy: Study suggests small molecule inhibitor RK-33 can block multiple variants of the SARS-CoV-2 virus from replicating

Based on findings from a new study by a Johns Hopkins Medicine-led research team, an effective means of fighting SARS-CoV-2, the virus that causes COVID-19, may be possible that circumvents the problem of waning immunity often observed when current vaccines deal with emerging COVID variants. The method uses a small molecule inhibitor (a molecule approximately 1 nanometer in size that inhibits specific interactions between proteins) called RK-33 to block the virus’s ability to take over a host cell’s “genetic manufacturing plant” and make copies of itself.

“To date, COVID-19 vaccines have relied on preventing the binding of a SARS-CoV-2 surface protein — called the spike protein — to host cells and enabling infection, but if the spike protein changes with new variants, a vaccine’s effectiveness may be weakened,” says study senior author Venu Raman, Ph.D., professor of radiology, oncology and pharmacology at the Johns Hopkins University School of Medicine. “In contrast, our study shows that RK-33’s antiviral capability is unaffected by spike protein mutations and remains consistent across four SARS-CoV-2 variants.”

The research was first posted online Aug. 25, 2022, in the journal Frontiers in Microbiology.

For several years, Raman and his colleagues have studied a protein known as DDX3 and its impact on cancer. DDX3 is a ribonucleic acid (RNA) helicase, a protein that unwinds the double-stranded RNA controlling many tumor cells, enabling the RNA’s genetic code to be read (or translated). This, in turn, leads to the creation of new cancer cells and malignant spread of the disease. Studies by Raman’s team and others have suggested that RK-33, a DDX3 inhibitor developed in the Raman laboratory, can slow down cancer progression by keeping RNA from unwinding for translation.

DDX3 protein also has been shown to help promote the infectivity of many RNA viruses, such as HIV and respiratory syncytial virus (RSV). Consequently, RK-33, the DDX3-inhibitor with great promise as a cancer fighter, is now being seriously considered for a second therapeutic function: a broad-spectrum antiviral agent.

“We know that many RNA viruses usurp the DDX3 helicase function of the host cell to facilitate their own replication,” says Raman. “When scientific studies revealed that small concentrations of RK-33 blocked replication and limited infectivity by human parainfluenza type 3 virus, RSV, dengue virus, Zika virus and West Nile virus — and potentially, HIV — our team decided to see whether RK-33 could work on SARS-CoV-2 as well.”

Along with testing RK-33’s impact on SARS-CoV-2 infectivity and reproduction, the researchers extended their study to determine if the inhibitory action observed was limited to specific variants of the virus or would be effective against multiple variants. They used RK-33 to target DDX3 in laboratory cells infected with four variants of SARS-CoV-2 — the original virus and the alpha, beta and delta variants.

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