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Title KIOM develops a cell-based high throughput screening platform for COVID RNA polymerase inhibitors
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Writer Manager Date 2022-02-03 Hits 144

KIOM develops a cell-based high throughput screening

platform for COVID RNA polymerase inhibitors

Extensive anti-COVID effects surpassing Remdisivir of Lycorine derived from the herb Lycoris radiata verified


The Infectious Disease Research Team (research leader: Gwon Seon-oh) at the Korea Institute of Oriental Medicine (KIOM / president: Lee Jin-Yong) successfully developed a cell-based high throughput screening platform for COVID polymerase inhibitors, and used the platform to discover a nature-derived substance that inhibits COVID polymerase.

The research outcome was published in leading international academic journals including Phytomedicine (IF=5.340), Biomedicines (IF=6.081), and Journal of Clinical Medicine (IF=4.242).

COVID polymerase: It is an RNA-dependent RNA polymerase (RdRp) that directly mediates the replication of COVID genome, and is an important action point of antiviral agents. Remdesivir, the first-in-class agent against COVID-19, was reported to have the action mechanism of inhibiting this.

The research team succeeded in developing the reporter assay for measuring the activation of cell-based COVID polymerase, overcoming the limitations of conventional technologies with which the high throughput screening (HTS) application needed for development of new drugs is impossible, and proved the possibility of the HTS application of a candidate inhibitor for COVID polymerase inhibitor.

Compared to the conventional cell-free system, this enables measurement of the activation of COVID polymerase in the virus genome cell culture based on the expression of reporter luciferase, as well as quantitative analysis of the effect of the antiviral substance suppressing the autoreproduction of virus genome.

By comparing the result with the effect of Remdesivir, approved by FDA for the treatment of COVID-19, it is possible to draw a candidate substance for treating new and variant coronaviruses with a high possibility for successful clinical trials.

The platform is operated by transforming the COVID polymerase expression vector and luciferase reporter vector in the HEK293T cell, measuring the expression of reporter luciferase, and determining the activation of polymerase. After handling the test materials, the activation of polymerase is examined to see whether it has decreased and this is used as an indicator for the evaluation of the effect.

The research team used the platform that it developed to confirm the non-nucleoside COVID polymerase inhibitor effect of Lycorine derived from Lycoris radiata, a herbal material.

Lycoris radiata (石蒜) is a perennial plant in the liliaceae family of the liliales order among monocotyledons. It is a herbal material listed in Compendium of Materia Medica (本草綱目) written by Li Shizhen in the Ming Dynasty in China, and is known to have antidotal and diuretic effects.

The team verified Lycorine’s effect surpassing that of Remdesivir by measuring its COVID polymerase inhibition effect.

Lycorine’s effect was about 4.5 times higher than that of Remdesivir in the test targeting MERS-CoV polymerase (IC50=1.387μM, Remdesivir IC50=6.484μM), and about 1.8 times higher in the test targeting SARS-CoV-2 polymerase (IC50=1.341μM, Remdesivir IC50=2.914μM).

Lycorine showed extensive anti-COVID effect greater than that of Remdesivir in virus infection test using such new and variant coronaviruses as MERS-CoV, SARS-CoV, and SARS-CoV-2, and this is attributed to Lycorine’s more potent polymerase inhibitor effect.

The result of the comparison of the binding activities between SARS-CoV-2 polymerase and Lycorine measured using in silico docking assay with that of Remdesivir showed that Lycorine inhibits the virus RNA replication by forming hydrogen bond with three types of amino acids including Asp623, Asn691, and Ser759 located in the major pocket of polymerase. The docking score of the hydrogen bond measured at -6.2 kcal/mol was higher than that of Remdesivir (4.7 kcal/mol), indicating the maintenance of a more powerful binding force.

Meanwhile, the research conducted until now remains in the nonclinical test stage, and safety evaluation including toxicity test is needed to advance to the clinical trial.

Dr. Gwon, the research director, said, “The new research outcome is highly significant because it establishes the research infrastructure for development of clinical technologies in Korean medicine for the prevention and treatment of new and variant virus infections including COVID-19, through an independent development of a high throughput screening platform for antiviral substances targeting new and variant coronavirus RNA-dependent RNA polymerase (RdRp) as the action target.”

President Lee Jin-Yong of KIOM said, “It is an outstanding case of building the screening platform for exploring the potential value of a therapeutic candidate in Korean medicine, which is highly likely to be used in the clinical practices related to new and variant coronaviruses. We will try hard to protect the healthy living of the public by carrying out research that can benefit them.”

The research was conducted as a major program of KIOM, an affiliate of the Ministry of Science and ICT, under the support of the National Research Council of Science and Technology’s support program for convergence research.




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