Suramin Interactions Across Biological Systems: From Molecular Targets to Therapeutic Implications.

Suramin is a century-old polysulfonated naphthylurea that remains a first-line treatment for early-stage human African trypanosomiasis (HAT). Remarkably, despite its age, suramin continues to draw attention because of its unusually broad spectrum of biological activities. Historically known as an antagonist of purinergic (P2) receptors and an inhibitor of extracellular enzymes, suramin has more recently been shown to interact with a range of intracellular and mitochondrial proteins. These include succinate dehydrogenase, the ADP/ATP carrier (AAC), the aspartate/glutamate carriers AGC1 and AGC2, carnitine O-acetyltransferase (CRAT), and the ATP-Mg/Pi carrier (APC2). Across these targets, suramin displays sub-micromolar to low-micromolar potencies, largely driven by electrostatic complementarity between its highly anionic sulfonate groups and basic nucleotide- or anion-binding regions of proteins. This extensive polypharmacology helps explain the diverse biological effects reported for suramin and supports its use as a valuable pharmacological probe of mitochondrial transport and metabolism. At the same time, its largeness and high negative charge limit oral bioavailability and brain penetration, prompting efforts to develop simplified analogues. This review brings together chemical, biological, and structural perspectives on suramin, highlighting opportunities for drug repurposing, transporter-focused drug design, and a better understanding of mitochondrial toxicity.