COVID-19 has been mutating and spreading ever since the pandemic plagued the world. Contrary to what people believe, this disease is far from resolved. SARS-CoV-2, the virus responsible for COVID-19, which causes a respiratory disease, was identified first in 2019. It spreads through droplets when people speak, sneeze, or cough.

Recently, a surge in COVID-19 cases has been reported across Asian countries. Considering its fatal effects on humans, primarily death makes it a deadly disease requiring a permanent and potent cure. Scientists have researched a molecule inhibitor, RK-33, that can fight the deadly virus.

Johns Hopkins Medicine-led research team finds potential cure for COVID-19

Johns Hopkins Medicine-led 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.

“Our results indicate that for the four SARS-CoV-2 variants we tested, RK-33 treatment of infected cells showed significant reductions in the viral load [the number of virus particles in a defined sample size], as much as a thousandfold,” says Raman. “Consistent with this finding, we saw a downregulation [reduction in production] of most SARS-CoV-2 proteins and genes, including the protein transmembrane serine protease 2 [TMPRSS2], which we know strongly participates in the infectivity and spread of coronaviruses.”

Raman adds that not only did RK-33 work with four different SARS-CoV-2 variants, the protein’s antiviral activity is unaffected by the mutations that created each of them.

“Vaccines designed against the spike protein of one SARS-CoV-2 variant may not be as effective if a new variant has a mutated spike protein,” he explains. “The ability of RK-33 to inhibit DDX3’s unwinding of viral RNA for translation is independent of the spike protein, so it should remain effective against most variants.”

Currently, Raman and his team are looking at RK-33 as an antiviral against the omicron variant of SARS-CoV-2. The researchers hope to publish their findings later this year.

Along with Raman, the Johns Hopkins Medicine members of the research team are Farhad Vesuna (joint study lead author), Robert Scharpf and Paul Winnard. Collaborators from the Virginia Polytechnic Institute and State University are Ivan Akhrymuk (joint study lead author), Kylene Kehn-Hall, Lauren Panny and Amy Smith. Shih-Chao Lin from the National Taiwan Ocean University also contributed to the study.

The research was supported by National Institutes of Health grant R01CA207208 and the Flight Attendant Medical Research Institute.

Raman holds a patent on the composition of RK-33. The other study authors report no conflicts of interest.

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Johns Hopkins Medicine
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The U.S. Food and Drug Administration Approved Drugs for COVID-19

Effective drug treatments are essential due to the emergence of new SARS-CoV-2 variants, such as JN.1 and its subvariants LF.7 and NB.1.8. The earlier the detection, the easier it is for healthcare professionals to prescribe the right treatments. There are types of approved treatments—FDA and emergency use authorization (EUA). FDA-approved medications undergo a longer process since rigorous safety and efficacy standards are emphasized before medication roll-outs.

Types of COVID-19 Treatments

During a public health emergency, the FDA employs emergency use authorization (EUA) as a tool to accelerate medical treatment and product availability. Since the advent of the COVID-19 pandemic,  two vaccines—Pfizer-BioNTech and Moderna, as well as one treatment—Gilead Science’s remdesivir have received receive full FDA approval. 

FDA Approved or Authorized Drugs for Patients with Mild to Moderate COVID-19

• Paxlovid (nirmatrelvir and ritonavir) 
• Lagevrio (molnupiravir) 
• Veklury (remdesivir)

EUA Approved Treatments

• Antiviral Drugs
• Monoclonal Antibodies (mAbs) targeting SARS-COV-2
• Immune Modulators
• Renal Replacement Therapy Solutions

FDA Approved or Authorized Drugs or Renal Replacement Therapy Solutions to Treat or Support Patients Hospitalized Due to COVID-19

• Actemra (tocilizumab)
• Fresenius Medical multiFiltrate/multiBic/multiPlus replacement solutions
• Kineret (anakinra)
• Olumiant (baricitinib)
• Veklury (remdesivir)
• Gohibic (vilobelimab)
• Regiocit replacement solution

The Fight Against COVID-19 Continues

The relentless mutation of SARS-CoV-2 continues to pose a significant global health threat. However, studies such as Johns Hopkins Medicine’s introduction of RK-33 serve as a potential cure and fight against COVID-19. While further studies, including those on the Omicron variant, are presently underway, current FDA-approved and EUA-approved drug treatments help combat present and future COVID-19 variants. This paves the way for next-generation antiviral strategies with durable, mutation-resilient potential.