Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention of malaria), and is also used (combined with sulfadiazine) in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals. Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa. It has also found to inhibit SOD1, a key protein involved in ALS. Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce the effectiveness of pyrimethamine. These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.
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