Aspergillus-derived indole diketopiperazines (IDKPs): chemical diversity, biosynthetic logics, and therapeutic potential.
Indole diketopiperazine (IDKP) alkaloids are widely recognized as an important class of rigid three-dimensional scaffolds in microbial secondary metabolism and possess a broad spectrum of biological properties with therapeutic potential. For the past over half-century, great achievements had been made in discovery, biosynthetic characterization, and pharmacological investigation of novel IDKPs from the genus Aspergillus. However, despite the increasing number of reported compounds and growing understanding of their biosynthetic pathways, a systematic overview specifically focusing on Aspergillus-derived IDKPs remains lacking. Herein, we provide a comprehensive overview of Aspergillus-derived IDKPs (1-444), integrating their occurrence, structural diversity, biosynthetic logic, and biological activities. Beyond summarizing the reported metabolites, this review emphasizes the unique capacity of Aspergillus species to generate structurally diverse IDKPs and highlights the potential of genome mining and biosynthetic gene cluster (BGC) analysis for uncovering previously unexplored IDKP biosynthetic pathways. Current challenges and future perspectives associated with expanding the chemical diversity and therapeutic potential of Aspergillus-derived IDKPs are also discussed.