Screening Autophagy-Related Compounds to Develop Therapeutics for COVID-19

Junior Associate Professor Kazuo Takayama and his research team used human airway organoids to screen for compounds associated with autophagy and found cycloheximide and thapsigargine to exhibit potent antiviral effects against SARS-CoV-2. Additional testing revealed that cycloheximide is also effective against six mutant strains of SARS-CoV-2 and other human coronaviruses. The results of this study have been published online in Molecular Pharmaceuticals On March 22, 2023.

Targeting host proteins involved in viral infection is an effective way to deal with viruses that mutate rapidly to produce new strains one by one. In this study, scientists attempted to find therapeutic agents for COVID-19 by focusing on autophagy. It is known that autophagy is closely associated with SARS-CoV-2 infection and elimination, making autophagy-related compounds potential candidates for the treatment of COVID-19.

The research team screened a library of autophagy-related compounds with airway organoids to identify compounds that could control SARS-CoV-2 infection. Among the 80 compounds tested, they found cycloheximide and thapsigargine to reduce infection efficiency in a dose-dependent manner.

Because cycloheximide showed greater antiviral efficacy than thapcigarine, they examined cycloheximide in detail. Cycloheximide also showed antiviral activity against six mutant strains of SARS-CoV-2, as well as against human coronaviruses, HCoV-229E and HCoV-OC43, indicating that cycloheximide has broad-spectrum anti-coronavirus activity. On the other hand, researchers have observed significant cycloheximide-induced toxicity in animal experiments due to its function as an inhibitor of protein synthesis.

Takayama believes that less toxic derivatives or similar compounds of cycloheximide that retain their antiviral effects hold promise if they are developed in the future. In this study, the team demonstrated the feasibility of drug screening using human airway organoids, thus hinting at the possibility of combining the method with much larger compound libraries for more comprehensive therapeutic drug discovery for COVID-19.