An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA
Jianyuan Zhao1, Jing Wang1, Xu Pang1
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, 100050, Beijing, PR China.
Abstract:
The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.
Insights
A novel microbial metabolite, APL-16-5, effectively targets influenza A virus (IAV) by inducing protein degradation. This discovery offers a promising new therapeutic strategy against drug-resistant influenza strains.
Area of Science:
- Microbiology
- Virology
- Biochemistry
Background:
- Emerging drug-resistant and highly pathogenic influenza A virus (IAV) strains necessitate novel therapeutic interventions.
- Current treatments face challenges due to resistance and pathogenicity.
Purpose of the Study:
- To discover and characterize novel anti-IAV microbial metabolites.
- To elucidate the mechanism of action for potential new IAV therapeutics.
Main Methods:
- Isolation of metabolite APL-16-5 from Aspergillus sp. CPCC 400735.
- Biochemical assays to determine binding targets (TRIM25 and IAV PA subunit).
- Assessment of TRIM25-mediated ubiquitination and proteasomal degradation of PA.
- In vivo efficacy studies in a mouse model of lethal IAV infection.
Main Results:
- APL-16-5 was identified as a potent inhibitor of IAV.
- APL-16-5 induces the degradation of the IAV PA subunit via the ubiquitin-proteasome system.
- The metabolite demonstrated significant protection in mice against lethal IAV challenge.
- APL-16-5 functions as a proteolysis targeting chimera (PROTAC).
Conclusions:
- APL-16-5 is a natural microbial metabolite with potent in vivo anti-IAV activity.
- Its mechanism involves targeted protein degradation, offering a new therapeutic avenue.
- Medicinal chemistry can be employed to optimize APL-16-5 for enhanced anti-IAV potency and specificity.
