Suramin is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat African sleeping sickness and

river blindness Onchocerciasis, also known as river blindness, is a disease caused by infection with the parasitic worm ''Onchocerca volvulus''. Symptoms include severe itching, bumps under the skin, and blindness. It is the second-most common cause of blindne ...

. It is the treatment of choice for sleeping sickness without

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

involvement. It is given by injection into a vein. Suramin causes a fair number of side effects. Common side effects include nausea, vomiting,

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, headache, skin tingling, and weakness. Sore palms of the hands and soles of the feet, trouble seeing,

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

, and abdominal pain may also occur. Severe side effects may include low blood pressure, decreased level of consciousness,

kidney problems Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

, and low blood cell levels. It is unclear if it is safe when

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. Suramin was made at least as early as 1916. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In the United States it can be acquired from the

Centers for Disease Control The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, ...

(CDC). In regions of the world where the disease is common suramin is provided for free by the

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

(WHO).

Medical uses

Suramin is used for treatment of human

sleeping sickness African trypanosomiasis is an insect-borne parasitic infection of humans and other animals. Human African trypanosomiasis (HAT), also known as African sleeping sickness or simply sleeping sickness, is caused by the species '' Trypanosoma b ...

caused by trypanosomes. Specifically, it is used for treatment of first-stage African trypanosomiasis caused by '' Trypanosoma brucei rhodesiense'' and ''

Trypanosoma brucei gambiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extrace ...

'' without involvement of central nervous system. It is considered first-line treatment for '' Trypanosoma brucei rhodesiense'', and second-line treatment for early-stage ''

'', where

pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, '' Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypa ...

is recommended as first line. It has been used in the treatment of

(onchocerciasis).

Pregnancy and breastfeeding

It is unknown whether it is safe for the baby when a woman takes it while breastfeeding.

Adverse reactions

The most frequent adverse reactions are nausea, vomiting, diarrhea, abdominal pain, and a feeling of general discomfort. It is also common to experience various sensations in the skin, from crawling or tingling sensations, tenderness of palms and the soles, and numbness of hands, arm, legs or feet. Other skin reactions include skin rash, swelling and stinging sensation. Suramin can also cause loss of appetite and irritability. Suramin causes non-harmful changes in urine during use, specifically making the urine cloudy. It may exacerbate

kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an Inflammation, inflammatory kidney disease and has several types according to the location of the inflammation. Infla ...

. Less common side effects include extreme fatigue, ulcers in the mouth, and painful tender glands in the neck, armpits and groin. Suramin uncommonly affects the eyes causing watery eyes, swelling around the eyes, photophobia, and changes or loss of vision. Rare side effects include hypersensitivity reactions causing difficulty breathing. Other rare systemic effects include decreased blood pressure, fever, rapid heart rate, and convulsions. Other rare side effects include symptoms of liver dysfunction such as tenderness in upper abdomen, jaundice in eyes and skin, unusual bleeding or bruising. Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition.

Pharmacology

Pharmacokinetics

Suramin is not orally bioavailable and must be given intravenously. Intramuscular and subcutaneous administration could result in local tissue inflammation or necrosis . Suramin is approximately 99-98% protein bound in the serum and has a half-life of 41–78 days average of 50 days; however, the pharmacokinetics of suramin can vary substantially between individual patients. Suramin does not distribute well into cerebral spinal fluid and its concentration in the tissues is equivalently lower than its concentration in the plasma. Suramin is not extensively metabolized and about 80% is eliminated via the kidneys.

Mechanism of action

The mechanism of action for suramin is unclear, but it is thought that parasites are able to selectively uptake suramin via receptor-mediated endocytosis of drug that is bound to low-density lipoproteins and, to a lesser extent, other serum proteins. Once inside parasites, suramin combines with proteins, especially trypanosomal

glycolytic Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

enzymes, to inhibit energy metabolism.

Chemistry

The molecular formula of suramin is C₅₁H₄₀N₆O₂₃S₆. It is a

symmetric Symmetry () in everyday life refers to a sense of harmonious and beautiful proportion and balance. In mathematics, the term has a more precise definition and is usually used to refer to an object that is invariant under some transformations ...

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

in the center of which lies a

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

(NH–CO–NH) functional group. Suramin contains six aromatic systems – four

benzene ring Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal ring with one hydrogen atom attached to each. Because it contains only carbon and hydr ...

s, sandwiched by a pair of

naphthalene Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white Crystal, crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 Parts-per notation ...

moieties – plus four

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...

s (in addition to the urea) and six

sulfonic acid In organic chemistry, sulfonic acid (or sulphonic acid) refers to a member of the class of organosulfur compounds with the general formula , where R is an organic alkyl or aryl group and the group a sulfonyl hydroxide. As a substituent, it is kn ...

groups. When given as a medication, it is usually delivered as the sodium

sulfonate In organosulfur chemistry, a sulfonate is a salt, anion or ester of a sulfonic acid. Its formula is , containing the functional group , where R is typically an organyl group, amino group or a halogen atom. Sulfonates are the conjugate bases of ...

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

as this formulation is water-soluble, though it does deteriorate rapidly in air. The

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of organi ...

of suramin itself and

structural analog A structural analog, also known as a chemical analog or simply an analog, is a chemical compound, compound having a chemical structure, structure similar to that of another compound, but differing from it in respect to a certain component. It can ...

s is by successive formation of the amide bonds from their corresponding

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

(

aniline Aniline (From , meaning ' indigo shrub', and ''-ine'' indicating a derived substance) is an organic compound with the formula . Consisting of a phenyl group () attached to an amino group (), aniline is the simplest aromatic amine. It is an in ...

) and

carboxyl In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl group (e.g. ...

(as

acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

) components. Various routes to these compounds have been developed, including starting from separate naphthalene structures and building towards an eventual unification by formation of the urea or starting with a urea and appending successive groups.

History

Suramin was first made by the chemists Oskar Dressel, Richard Kothe and Bernhard Heymann at

Bayer AG Bayer AG (English: , commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and is one of the largest pharmaceutical companies and biomedical companies in the world. Headquartered in Leverkusen, Bayer's ...

laboratories in

Elberfeld Elberfeld is a municipal subdivision of the Germany, German city of Wuppertal; it was an independent town until 1929. History The first official mentioning of the geographic area on the banks of today's Wupper River as "''elverfelde''" was ...

, after research on a series of urea-like compounds. The drug is still sold by Bayer under the

brand name A brand is a name, term, design, symbol or any other feature that distinguishes one seller's goods or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create and ...

Germanin. The chemical structure of suramin was kept secret by Bayer for commercial and strategic reasons, but it was elucidated and published in 1924 by Ernest Fourneau and his team at the

Pasteur Institute The Pasteur Institute (, ) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines for anthrax and rabies. Th ...

Research

It is also used as a research

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

to inhibit the activation of heterotrimeric G proteins in a variety of GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including

rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...

, the A1 adenosine receptor, the

D2 receptor Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, ...

, the P2 receptor, and

ryanodine receptor Ryanodine receptors (RyR) make up a class of high-conductance, intracellular calcium channels present in various forms, such as animal muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...

s. Suramin is also an inhibitor of ABC-type and P-type ATPases, which acts competitively with ATP. Suramin was studied as a possible treatment for

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

in a clinical trial. Suramin has been studied in a mouse model of

autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

and in a small phase I/II human trial. Secondary outcomes showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.The safety and activity of low‐dose suramin showed promise as a novel approach to treatment of ASD in this small study. Results from a randomized clinical study found no statistically significant effects of suramin (in either 10mg or 20mg doses) versus placebo on boys with moderate to severe autism spectrum disorder. Suramin is a reversible and competitive protein tyrosine phosphatase (PTPases) inhibitor, also is the potent inhibitor of

sirtuin Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins ...

s, purified

topoisomerase II Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of Adenosine triphosphate, ATP, unlike Type I topoisomerase. In this process, t ...

and SARS-CoV-2

RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the self-replication, replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand Complementarity (molecular biology), compleme ...

(RdRp).

References

External links

Suramin sodium
National Cancer Institute {{Portal bar, Medicine 1916 in science Anthelmintics Antiprotozoal agents Drugs developed by Bayer Benzanilides Naphthalenesulfonic acids Ureas World Health Organization essential medicines Wikipedia medicine articles ready to translate