Ribosomally Synthesized Fungal Peptides: Biosynthetic Engineering for Targeted Anticancer ADC Payloads

Fungal ribosomally synthesized and post-translationally modified peptides (F-RiPPs) embody a paradoxical duality, transitioning from lethal mycotoxins to precision oncology payloads via antibody-drug conjugates (ADCs). This review portrays the biosynthetic logic of canonical families - amatoxins/phallotoxins, dikaritins, epichloëcyclins, and emergent asperigimycins, emphasizing PTMs like macrocyclization, N-methylation, and oxidative cross-links that confer proteolytic stability, membrane permeability, and target affinity. Genome mining pipelines integrating antiSMASH, seq2ripp, HypoRiPPAtlas, and GNPS molecular networking accelerate cryptic BGC decryption, heterologous expression in yeast/filamentous fungi, and combinatorial refactoring for analog libraries. Pharmacologically, F-RiPPs inhibit RNA Pol II (amatoxins), disrupt microtubules (dikaritins), perturb membranes (borosins), and induce lipid-mediated apoptosis (asperigimycins), with preclinical IC50s of 1–50 nM/μM and therapeutic indices >100 in xenografts. Translational exemplars include Heidelberg Pharma's ATACs, achieving Phase I/IIa remissions in myeloma/NHL via BCMA/CD37-targeted amanitin delivery. Addressing bottlenecks in silent cluster activation, enzyme mechanistics, and GMP-scaleup, a roadmap proposes ML-driven prioritization and automated heterologous platforms to harness untapped RiPP diversity for MDR-evasive, bystander-active therapeutics.