Japanese scientists expand stockpile of drugs to fight COVID-19

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has dealt a devastating blow to the world
.
Although vaccination programs are advancing, pharmacotherapy for COVID-19 is still very important
for patients.
Now, a research team led by Tokyo Medical and Dental University (TMDU) has designed and synthesized compounds that promise to become novel drugs
targeting SARS-CoV-2.

The SARS-CoV-2 virus contains an enzyme called a master protease (Mpro), which cleaves other proteins
encoded by the SARS-CoV-2 genome.
When designing COVID-19 drugs, Mpro is an attractive target because it is essential for viral replication and is very different from human molecules, so drugs that target Mpro may have few side effects and high
efficacy.

While testing a group of compounds known to have inhibitory activity against the 2002 SARS-CoV virus, the research team identified a compound called 5h, which showed activity to inhibit SARS-CoV-2 Mpro, but was inefficient and unstable
.

Therefore, they used 5h as a starting point to develop other compounds in hopes of improving efficiency and stability
.
Lead author Kohei Tsuji explains: "Our strategy is to introduce fluorine atoms into the molecular part responsible for inhibiting Mpro to increase its binding affinity and replace the chemical bonds in 5h with different structures to improve its biological stability
.
”

Senior author Hirokazu Tamamura explains: "Among the compounds we developed, compound 3 showed high potency in blocking SARS-CoV-2 infection in vitro without any viral breakthrough
.
Compound 4, a derivative of Compound 3, replaces one of the easily broken amide bonds with a stable sulfamide bond and also shows significant anti-SARS-CoV-2 activity
.
”

According to him, although the Mpro inhibitory activity of compound 4 is lower than that of compound 3, the improved stability means that the overall activity of compound 4 is comparable
to compound 3.

They later tested the novel compounds on multiple SARS-CoV-2 strains and found that compound 3 was equally effective
against the mutant strain and the original strain.
In addition, neither compound 3 nor compound 4 is toxic
to cell cultures.
The above data suggest that these compounds have great potential
in the treatment of COVID-19.

Drug selection stocks are important for the treatment of diseases, so it is important
to develop highly effective drugs against the novel SARS-CoV-2 virus.
This work identifies two compounds that are promising to become drugs, and development work on these compounds continues
.
Overall, this is an important advance
, both in the broad field of drug development and in the treatment of COVID-19.

Original search

Potent and biostable inhibitors of the main protease of SARS-CoV-2.
 

iScience, 2022; 25 (11): 105365 DOI: 10.
1016/j.
isci.
2022.
105365