El tratamiento con RK-33 de las células infectadas redujo significativamente la carga viral.
Según una investigación realizada por Johns Hopkins Medicine, múltiples variantes del[{” attribute=””>SARS-CoV-2 virus can be blocked from replicating by the small molecule inhibitor RK-33.
An efficient method of combating SARS-CoV-2, the virus that causes COVID-19, may be possible based on findings from a recent study by a research team led by Johns Hopkins Medicine that avoids the issue of waning immunity that is frequently noticed when current vaccines address emerging COVID variants. The technique stops the virus’s ability to take over a host cell’s “genetic manufacturing plant” and replicate itself by using a tiny molecule inhibitor called RK-33. This molecule, which has a size of around 1 nanometer, inhibits certain interactions between proteins.
“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 recently published in Frontiers in Microbiology.
Cutaway view (left) of SARS-CoV-2, the virus that causes COVID-19, showing its double-stranded RNA genome. During infection, the virus takes over a host cell’s DDX3 RNA helicase protein (right) to unwind the viral RNA and enable it to be copied. A new study shows that a Johns Hopkins Medicine-created protein, RK-33, can prevent DDX3 from carrying out this function. Credit: Graphic created by M.E. Newman, Johns Hopkins Medicine, using SARS-CoV-2 graphic courtesy of Davian Ho for the Innovative Genomics Institute and DDX3 graphic courtesy of the Small Angle Scattering Biological Data Bank. The scale of the virus to RK-33 is not proportional.
Raman and his colleagues have been researching the connection between a protein called DDX3 and cancer for a number of years. DDX3 is an RNA helicase, a protein that unwinds the double-stranded RNA that controls many tumor cells, allowing the RNA’s genetic code to be read (or translated). This results in the formation of new cancer cells and the malignant expansion of the disease. Studies conducted by Raman’s group and others have led to the belief that RK-33, a DDX3 inhibitor created in the Raman laboratory, may limit the development of cancer by preventing RNA from unwinding for translation.
The DDX3 protein has also been demonstrated to enhance the infectivity of numerous RNA viruses, including HIV and respiratory syncytial virus (RSV). RK-33, a DDX3 inhibitor that has shown remarkable promise in the battle against cancer, is thus being carefully examined for use as 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], tanto como mil veces”, dice Raman. “De acuerdo con este hallazgo, vimos una regulación a la baja [reduction in production] de la mayoría de las proteínas y genes del SARS-CoV-2, incluida la proteína transmembrana serina proteasa 2 [TMPRSS2]que sabemos que participa fuertemente en la infectividad y propagación de los coronavirus”.
Raman agrega que RK-33 no solo funcionó con cuatro variantes diferentes de SARS-CoV-2, sino que la actividad antiviral de la proteína tampoco se ve afectada por las mutaciones que crearon cada una de ellas.
“Las vacunas diseñadas contra la proteína espiga de una variante del SARS-CoV-2 pueden no ser tan efectivas si una nueva variante tiene una proteína espiga mutada”, explica. “La capacidad de RK-33 para inhibir el desenrollado del ARN viral de DDX3 para la traducción es independiente de la proteína de pico, por lo que debería seguir siendo eficaz contra la mayoría de las variantes”.
Actualmente, Raman y su equipo están analizando el RK-33 como un antiviral contra la variante omicron del SARS-CoV-2. Los investigadores esperan publicar sus hallazgos a finales de este año.
Referencia: “RK-33, un inhibidor de molécula pequeña de la ARN helicasa DDX3 del huésped, suprime múltiples variantes de SARS-CoV-2” por Farhad Vesuna, Ivan Akhrymuk, Amy Smith, Paul T. Winnard Jr, Shih-Chao Lin, Lauren Panny , Robert Scharpf, Kylene Kehn-Hall y Venu Raman, 25 de agosto de 2022, Fronteras en Microbiología.
DOI: 10.3389/fmicb.2022.959577
La investigación fue apoyada por la subvención R01CA207208 de los Institutos Nacionales de Salud y el Instituto de Investigación Médica de Asistentes de Vuelo.
Raman posee una patente sobre la composición de RK-33. Los otros autores del estudio informan que no tienen conflictos de intereses.
