Use of induced pluripotent stem cells to find new drugs for COVID-19

FEBS Open Bio (2021). DOI: 10.1002 / 2211-5463.13153 “width =” 800 “height =” 530 “/>
Complex screening using SeV and iPSCs. (A) Construction of SeV. The SeV carrying the EGFP gene in the 3 ‘region of the viral genomic RNA was constructed after removal of the F gene. (B) Timeline of complex review. (C) Complex screening scheme. (D and E) Result of first examination. Approximately 500 compounds were evaluated. The blue dot indicates a negative control (DMSO). The red spots indicate the affected drugs raloxifene, rifampin, pranlukast, zileuton and pioglitazone. (F) List of affected compounds. The results reflect the number of EGFP positive cells. Credit: FEBS Open Bio (2021). DOI: 10.1002 / 2211-5463.13153

An intensive study of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, was recorded worldwide last year. Despite several vaccines already available, the rapid mutation of the virus raises concerns that the infection will continue to spread. A new study led by CiRA professor Haruhisa Inoue shows that induced pluripotent stem cells (iPS) can help find effective cures for RNA viruses.

HIV, the Ebola virus and now the SARS-CoV-2 pandemic, in the last half century, RNA viruses are responsible for many of the biggest health accidents in society. One of the big challenges in managing these viruses is rapid mutation. In fact, it is possible that SARS-Cov-2 will continue to mutate, it may need, like the flu, new vaccines a year.

Inoue and his colleagues suggested screening drugs that use different types of RNA viruses and cells as a possible solution.

“The usual therapeutic approach for RNA viruses, such as penicillin for bacterial infections, is needed not only to treat current RNA viruses but also new ones,” Inoue said. “Drugs that are effective in different combinations of RNA virus and cells may have therapeutic potential for future RNA virus infections. We reviewed approved drugs that prevent Sendai virus infection in iPS cells and used them to test whether they could prevent Ebola virus and SARS- CoV- infection. 2 in different cell types. “

Where drug detection involves screening thousands of chemicals for which we know little about effects on humans, drug conversion is testing drugs for which safety is already known. This approach can find drug candidates faster than drug detection.

Sendai virus is an RNA virus commonly used in iPS cell research, and unlike Ebola and SARS-CoV-2 viruses, experiments do not require biosafety laboratories.

From a review of 500 drugs, five showed promise for further research, including Raloxifene, a drug for breast cancer and osteoporosis, and Pioglitazone, a drug for diabetes mellitus.

Although iPS cells are susceptible to Sendai virus infection, they lack a key receptor that interferes with SARS-CoV-2 infection.

“Research has shown that SARS-CoV-2 infects cells by binding to ACE2 [angiotensin-converting enzyme 2]. SARS-CoV-2 target cells express a higher level of this receptor, but iPS cells express a low level, “Inoue explained.

Therefore, in order to investigate these drugs in Ebola virus and SARS-CoV-2 infection, the study transferred iPS cells to other human and monkey cells. Consistent with the effects on Sendai virus, raloxifene has been shown to have antiviral activity against Ebola virus and SARS-CoV-2.

Raloxifene is a selective estrogen receptor modulator (SERM), a group of drugs commonly used to treat breast cancer and postmenopausal symptoms such as menopause. The scientists therefore investigated other SERMSs, finding three more that had inhibitory effects on the Ebola virus and SARS-CoV-2 infection.

Pioglitazone, on the other hand, had milder benefits for preventing SARS-CoV-2 infection, but did not have any Ebola virus infections. However, the combination of the two drugs had a mild synergistic effect on SARS-CoV-2 infection.

“These drugs, which have different efficacy for RNA viruses and cells, may have therapeutic potential for RNA virus infections, including emerging and mutated viruses,” Inoue said.


New candidate for drugs against COVID-19


More information:
Keiko Imamura et al. iPSC drug conversion screening identifies anti-RNA virus agents that modulate the sensitivity of host cells, FEBS Open Bio (2021). DOI: 10.1002 / 2211-5463.13153

Provided by Kyoto University

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