Suramin

Suramin , according to PubChem annotation, is used parenterally in the treatment of African trypanosomiasis. The featured image comes from PubChem and the Wikipedia page of P2Y receptors. PubChem annotation claims that it binds numerous peptide growth factors preventing them from binding to their receptors. Is it any wonder that suramin is not given orally to treat African sleeping sickness? The molecule is a huge, charged polyamine (many blue Nitrogens in the featured image.) Suramin is presumably a P2Y receptor inhibitor. Is there any P2Y receptor antagonist that affects lysosome pH?

2017 Autism Trial [1]

from the introduction… Suramin has many actions.

• an inhibitor of purinergic signaling. It is the oldest member of a growing class of antipurinergic drugs (APDs) in development
• first synthesized in 1916 to treat African sleeping sickness (trypanosomiasis),
• increased 5 times or more over several months has been used to treat AIDS or kill cancer cells during chemotherapy.
• levels were maintained over 150 μmol/L for 3–6 months at a time to treat cancer, a number of dose‐limiting side effects occurred: adrenal insufficiency, anemia, and peripheral neuropathy.
• Low dose to achieve blood levels of about 5–10 μM was effective in treating ASD‐like symptoms and did not produce toxicity even when used for at least 4 months.

Suramin affects many metabolic pathways.

Inositols do not seem to be on this list.

Suramin was shown to be safe at low dose. Small changes were seen in social scores. Numerous pathways were effect as witnessed by variables of importance (VIP) scores. The point is that a molecule like suramin that can bind many things may affect many pathways. The encouraging part is that very low doses elicited an effect.

Adenosine receptors in neuro development [2]

The 2017 suramin clinical trial [1] was cited by a review published the same year. Going back to the featured image, these are some comments on the various members of the P2Y family in regards to the central nervous system (CNS)

• Family members include P2Y_{1, 2, 4, 6, 11, 12, 13, 14}
• Purine nucleosides exert receptor-mediated actions in all mammalian tissues and systems, including the brain.
• P1 receptors (A_{1, 2A, 2B, 3} subtypes) are activated by adenosine. Point of interest is that caffeine is an antagonist of the adenosine A2_A receptor.
• Extracellular guanosine may also modulate brain functions.
• Some specific subtypes are also crucially involved in controlling brain development.

This review gives the impression that surimin may have multiple targets even with the rather broad category of PY2 receptors.

The 2023 Suramin for ASD clinical trial…

A 14 week, randomized, double-blind, placebo-controlled proof -of-concept study (n = 52) was conducted to test the efficacy and safety of suramin intravenous infusions in boys aged 4–15 years with moderate to severe ASD. The study had 3 treatment arms: 10 mg/kg suramin, 20 mg/kg suramin, and placebo given at baseline, week 4, and week 8. The Aberrant Behavior Checklist of Core Symptoms (ABC-Core) (subscales 2, 3, and 5) was the primary outcome marker. The Clinical Global Impressions—Improvement (CGI-I) was a secondary endpoint.

This post is not going to go into all of the data in this clinical trial. They had some adverse events, but the conclusion was that the product was safe.

In my opinion a short coming of this study is that we have no idea as to the mechanism of action. Which P2Y receptor(s). If suramin were just a dietary ingredient a slight improvement, albeit not significant statistically, would be a big deal. Since this compound involves needles and a long half life in the body, things are a bit different, in my opinion. A PubMed search was performed to determine if any P2Y receptor was involved in lysosome function.

P2Y₁₂ Receptor Antagonist Ticagrelor quick note [4]

Ticagrelor is a P2Y12 Platelet Inhibitor. The mechanism of action of ticagrelor is as a P2Y12 Receptor Antagonist, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor. The physiologic effect of ticagrelor is by means of Decreased Platelet Aggregation.

The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4^-/- mouse model of Stargardt’s disease, an early onset retinal degeneration. Lowering lysosomal pH through cAMP-dependent pathways decreases accumulation of autofluorescent material in RPE cells in vitro, but identification of an appropriate receptor is crucial for manipulating this pathway in vivo. As the P2Y₁₂ receptor for ADP is coupled to the inhibitory G_i protein, we asked whether blocking the P2Y₁₂ receptor with ticagrelor could restore lysosomal acidity and reduce autofluorescence in compromised RPE cells from ABCA4^-/- mice. Oral delivery of ticagrelor giving rise to clinically relevant exposure lowered lysosomal pH in these RPE cells. Ticagrelor also partially reduced autofluorescence in the RPE cells of ABCA4^-/- mice. In vitro studies in ARPE-19 cells using more specific antagonists AR-C69931 and AR-C66096 confirmed the importance of the P2Y₁₂ receptor for lowering lysosomal pH and reducing autofluorescence. These observations identify P2Y₁₂ receptor blockade as a potential target to lower lysosomal pH and clear lysosomal waste in RPE cells. [4]

Lu 2018

Suramin, so what?

It would be easier to get excited about any of this P2Y antagonists, even the specific ones, if we knew were else they are acting.

References

1. Naviaux R. K., Curtis B., Li K., Naviaux J. C., Bright A. T., Reiner G. E. (2017). Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann. Clin. Transl. Neurol. 4, 491–505. 10.1002/acn3.424 [PMC free article]
2. Fumagalli M, Lecca D, Abbracchio MP, Ceruti S. Pathophysiological role of purines and pyrimidines in neurodevelopment: unveiling new pharmacological approaches to congenital brain diseases. Front Pharmacol. 2017;8:941. 1. [PMC free article]
3. Hough D, Mao AR, Aman M, Lozano R, Smith-Hicks C, Martinez-Cerdeno V, Derby M, Rome Z, Malan N, Findling RL. Randomized clinical trial of low dose suramin intravenous infusions for treatment of autism spectrum disorder. Ann Gen Psychiatry. 2023 Nov 6;22(1):45. PMC free article
4. Lu W, Gómez NM, Lim JC, Guha S, O’Brien-Jenkins A, Coffey EE, Campagno KE, McCaughey SA, Laties AM, Carlsson LG, Mitchell CH. The P2Y₁₂ Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4^-/- Mouse Model of Retinal Degeneration. Front Pharmacol. 2018 Apr 19;9:242. PMC free article