Three bodies of drug repurposing literature have developed in parallel without mechanistic integration: antifungal drugs demonstrating anticancer activity, cancer drugs inhibiting fungal hyphal morphogenesis, and cholesterol-trafficking inhibitors blocking viral replication. This perspective proposes that these overlapping pharmacologies share a single underlying vulnerability: the sterol-sensing-domain (SSD) protein family and its associated lipid-transfer machinery, including NPC1, NPC1L1, Patched, SCAP, HMG-CoA reductase, OSBP, and fungal ERG enzymes. Evidence from cryo-electron microscopy, chemogenomic screens, clinical trials in basal cell carcinoma, and antiviral studies of enteroviruses, Ebola, and coronaviruses converges on this framework. A candidate drug class is identified whose members demonstrate activity across all three domains, with itraconazole as the prototype. A metallomics layer is proposed linking SSD-protein function to trace metal cofactors. Bradford Hill criteria are adapted for evaluating the tri-convergence hypothesis. Implications for intratumor mycobiome and virome research are discussed.
Karen Pendergrass (Tue,) studied this question.