SB43154 drug used in cancer research shows promise against COVID-19 in preclinical studies: Scientists
Remarkably, even after more than 50 consecutive generations exposed to the drug, the virus was unable to develop resistance. Scientists from the Indian Council of Medical Research (ICMR) and Indian Council of Agricultural Research (ICAR) have jointly found that the drug -- SB431542, an ALK5 inhibitor -- is highly effective against the coronavirus.
Study findings
This discovery was a collaborative effort between the National Centre for Veterinary Type Culture in Hisar and National Institute of Virology (NIV) under the ICMR in Pune, said NIV Director Dr Naveen Kumar.
The study was first released as a preprint on bioRxiv and has since been accepted for publication in the Journal of Virology. If future human trials confirm its effectiveness, the drug could become a groundbreaking tool in the fight against COVID-19.
Since December 2019, when the coronavirus emerged from China's Wuhan, it has spread to nearly every country in the world. Since 2020, more than 30 anti-Covid vaccines have received the World Health Organization's (WHO) approval for global use.
"However, health experts believe vaccines alone are not enough. The virus continues to mutate, and many existing treatments like Remdesivir and monoclonal antibodies will quickly lose effectiveness," Kumar said.
In this context, Indian scientists have been screening small molecule inhibitors that mainly target cellular kinases and phosphatases. One such compound, SB431542 -- originally developed to block TGF-β (Transforming Growth Factor-beta) signalling and commonly used in preclinical cancer, inflammation and fibrosis research -- has now been found by Indian researchers to also inhibit the coronavirus effectively.
Kumar explained that SB431542 fights the virus in three fronts. It first blocks the virus from entering human cells by targeting the TGF-β/Smad pathway. Secondly, it disrupts the ability of the virus to assemble inside cells by interfering with ORF3a-related lysosomal dysfunction. Finally, it prevents the virus from killing the infected cell (a process called apoptosis), which helps stop the virus from escaping and spreading to other cells. This three-pronged approach has not been observed in any existing antiviral drug.
Interestingly, the drug acted through both direct and indirect mechanisms -- it directly targets the viral ORF3a protein and indirectly hinders the virus by blocking the host cell's TGF-β signaling pathway.
SB431542 was also tested against the chicken coronavirus (Infectious Bronchitis Virus or IBV) in specific pathogen-free chicken embryos. Embryos treated with the drug developed normally and showed no mortality, while those in the untreated control group failed to develop properly and did not survive.
Kumar emphasised that even after exposing the virus to the drug over 50 successive generations (passage), it failed to develop resistance. This suggests that the chances of the virus evolving a drug-resistant variant against this compound are extremely low. This is a major advancement over existing antivirals like Remdesivir, against which the virus builds resistance quickly.
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