Newswise — Primarily based on findings from a brand new examine by a Johns Hopkins Medication-led analysis crew, an efficient technique of preventing SARS-CoV-2, the virus that causes COVID-19, could also be potential that circumvents the issue of waning immunity usually noticed when present vaccines cope with rising COVID variants. The tactic makes use of a small molecule inhibitor (a molecule roughly 1 nanometer in dimension that inhibits particular interactions between proteins) referred to as RK-33 to dam the virus’s potential to take over a number cell’s “genetic manufacturing plant” and make copies of itself.
“To this point, COVID-19 vaccines have relied on stopping the binding of a SARS-CoV-2 floor protein — referred to as the spike protein — to host cells and enabling an infection, but when the spike protein adjustments with new variants, a vaccine’s effectiveness could also be weakened,” says examine senior writer Venu Raman, Ph.D., professor of radiology, oncology and pharmacology on the Johns Hopkins College Faculty of Medication. “In distinction, our examine reveals that RK-33’s antiviral functionality is unaffected by spike protein mutations and stays constant throughout 4 SARS-CoV-2 variants.”
For a number of years, Raman and his colleagues have studied a protein referred to as DDX3 and its impression on most cancers. 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 learn (or translated). This, in flip, results in the creation of latest most cancers cells and malignant unfold of the illness. Research by Raman’s crew and others have instructed that RK-33, a DDX3 inhibitor developed within the Raman laboratorycan decelerate most cancers development by holding RNA from unwinding for translation.
DDX3 protein has additionally been proven to assist promote the infectivity of many RNA viruses, corresponding to HIV and respiratory syncytial virus (RSV). Consequently, RK-33, the DDX3-inhibitor with nice promise as a most cancers fighter, is now being severely thought-about for a second therapeutic perform: a broad-spectrum antiviral agent.
“We all know that many RNA viruses usurp the DDX3 helicase perform of the host cell to facilitate their very own replication,” says Raman. “When scientific research revealed that small concentrations of RK-33 blocked replication and restricted infectivity by human parainfluenza sort 3 virus, RSV, dengue virus, Zika virus and West Nile virus — and probably, HIV — our crew determined to see whether or not RK-33 may work on SARS-CoV-2 as effectively.”
Together with testing RK-33’s impression on SARS-CoV-2 infectivity and copy, the researchers prolonged their examine to find out whether or not the inhibitory motion noticed was restricted to particular variants of the virus or could be efficient towards a number of variants. They used RK-33 to focus on DDX3 in laboratory cells contaminated with 4 variants of SARS-CoV-2 — the unique virus and the alpha, beta and delta variants.
“Our outcomes point out that for the 4 SARS-CoV-2 variants we examined, RK-33 remedy of contaminated cells confirmed important reductions within the viral load [the number of virus particles in a defined sample size], as a lot as a thousandfold,” says Raman. “In line with this discovering, we noticed a downregulation [reduction in production] of most SARS-CoV-2 proteins and genes, together with the protein transmembrane serine protease 2 [TMPRSS2]which we all know strongly take part within the infectivity and unfold of coronaviruses.”
Raman provides that not solely did RK-33 work with 4 completely different SARS-CoV-2 variants, the protein’s antiviral exercise is unaffected by the mutations that created every of them.
“Vaccines designed towards the spike protein of 1 SARS-CoV-2 variant is probably not as efficient if a brand new variant has a mutated spike protein,” he explains. “The power of RK-33 to inhibit DDX3’s unwinding of viral RNA for translation is unbiased of the spike protein, so it ought to stay efficient towards most variants.”
At the moment, Raman and his crew are taking a look at RK-33 as an antiviral towards the omicron variant of SARS-CoV-2. The researchers hope to publish their findings later this yr.
Together with Raman, the Johns Hopkins Medication members of the analysis crew are Farhad Vesuna (joint examine lead writer), Robert Scharpf and Paul Winnard. Collaborators from the Virginia Polytechnic Institute and State College are Ivan Akhrymuk (joint examine lead writer), Kylene Kehn-Corridor, Lauren Panny and Amy Smith. Shih-Chao Lin from the Nationwide Taiwan Ocean College additionally contributed to the examine.
The analysis was supported by the Nationwide Institutes of Well being grant R01CA207208 and the Flight Attendant Medical Analysis Institute.
Raman holds a patent on the composition of RK-33. The opposite examine authors report no conflicts of curiosity.