An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA

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.

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

“…The action mechanism of APL-16-5 was verified to be similar to that of a PROTAC degrader featuring the Hook effect. Interestingly, APL-16-5 remarkably inhibited IAV and blocked lethal IAV infection in mice . Thus, the microbial metabolite APL-16-5 has the potential to become a new anti-IAV agent with novel acting mode.…”

“…160 Recently, APL-16-5 was found to potently inhibit the influenza A virus (IAV) (EC 50 = 0.28 ± 0.01 μM in HEK293TGluc cells infected by IAV WSN/33 for 24 h) via suppressing de novo viral replication. 161 Further investigation showed that APL-16-5 exerted an antireplication effect by acting as a heterobifunctional molecule and binding to the IAV polymerase subunit PA and the E3 ligase tripartite motif containing 25 (TRIM25), resulting in the TRIM25-mediated ubiquitination of PA and its degradation by proteasomal means (2 and 10 μM in A549-5Ps cells, respectively, 24 h). The action mechanism of APL-16-5 was verified to be similar to that of a PROTAC degrader featuring the Hook effect.…”

“…Interestingly, APL-16-5 remarkably inhibited IAV and blocked lethal IAV infection in mice. 161 Thus, the microbial metabolite APL-16-5 has the potential to become a new anti-IAV agent with novel acting mode.…”

Discovery and Activation of the Cryptic Cluster from Aspergillus sp. CPCC 400735 for Asperphenalenone Biosynthesis

“…23 Intriguingly, asperphenalenones could inhibit the anti-influenza A virus (IAV), exhibiting extraordinary bioactivities with a novel mechanism. 24 The unique structures and conspicuous bioactivity of asperphenalenones encouraged us to mine more congeners. Here, we report (i) the overexpression of a pathway-specific regulator coding gene aspE within the asperphenlenons biosynthetic cluster asp; (ii) the isolation, characterization, and bioactivity determinations of 13 asperphenlenons including 11 new analogues; and (iii) the proposed biosynthetic pathway of the primary product asperphenlenone E. This study provides the approach to trigger down-regulated gene clusters by overexpressing pathway-specific regulator coding genes and assists to broaden our understanding on the biosynthetic mechanism and metabolic engineering of asperphenalenones.…”

“…These meroterpenoids comprise a linear diterpene attached to a phenalenone moiety via a C–C bond, implying that diterpene is derived from the terpenoid pathways . Intriguingly, asperphenalenones could inhibit the anti-influenza A virus (IAV), exhibiting extraordinary bioactivities with a novel mechanism . The unique structures and conspicuous bioactivity of asperphenalenones encouraged us to mine more congeners.…”