Suramin

BackgroundAutism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines-signaling molecules made in mitochondria-that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders.Objectives and methodsWe used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice.ResultsWe found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.ConclusionsHyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that originated in Wuhan, China, in December 2019 has impacted public health, society, the global economy, and the daily lives of billions of people in an unprecedented manner. There are currently no specific registered antiviral drugs to treat or prevent SARS-CoV-2 infections. Therefore, drug repurposing would be the fastest route to provide at least a temporary solution while better, more specific drugs are being developed. Here, we demonstrate that the antiparasitic drug suramin inhibits SARS-CoV-2 replication, protecting Vero E6 cells with a 50% effective concentration (EC50) of ∼20 μM, which is well below the maximum attainable level in human serum. Suramin also decreased the viral load by 2 to 3 logs when Vero E6 cells or cells of a human lung epithelial cell line (Calu-3 2B4 [referred to here as "Calu-3"]) were treated. Time-of-addition and plaque reduction assays performed on Vero E6 cells showed that suramin acts on early steps of the replication cycle, possibly preventing binding or entry of the virus. In a primary human airway epithelial cell culture model, suramin also inhibited the progression of infection. The results of our preclinical study warrant further investigation and suggest that it is worth evaluating whether suramin provides any benefit for COVID-19 patients, which obviously requires safety studies and well-designed, properly controlled randomized clinical trials.

Inhibition of angiogenesis through blocking of growth factors involved in this process could be a novel therapeutic approach in several important pathologies, neoplasia among them. Suramin has recently been described to possess antineoplastic activity in animals and humans, and it has been proposed that an important role in this activity is played by antagonism of growth factors and especially bFGF. To investigate this hypothesis in vivo, we used gelatin sponges loaded with bFGF and implanted subcutaneously in mice. Suramin showed an inhibitory activity on bFGF-induced angiogenesis, whereas it was inactive in the case of heparin-complexed bFGF. Suramin was also studied in an in vivo model of tumour-induced angiogenesis using the murine M5076 reticulosarcoma, a tumour producing significant levels of bFGF. Suramin was able to reduce tumour growth and tumour induced angiogenesis, and exogenous administration of bFGF countered suramin effects.

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.