Dihydrofolate reductase inhibitor
Encyclopedia
A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase
, and is a type of antifolate
.
Since folate is needed by rapidly dividing cells to make thymine
, this effect may be used to therapeutic advantage. For example, methotrexate
is used as cancer chemotherapy because it can prevent neoplastic cells from dividing. Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.
A variety of drugs act as inhibitors
of dihydrofolate reductase:
Dihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
, and is a type of antifolate
Antifolate
Antifolates are drugs that impair the function of folic acids. Many are used in cancer chemotherapy, some are used as antibiotics or antiprotozoal agents....
.
Since folate is needed by rapidly dividing cells to make thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
, this effect may be used to therapeutic advantage. For example, methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
is used as cancer chemotherapy because it can prevent neoplastic cells from dividing. Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of dihydrofolate reductase:
- the antibioticAntibioticAn antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
trimethoprimTrimethoprimTrimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
and its derivatives brodimoprimBrodimoprimBrodimoprim is a structural derivative of trimethoprim. In brodimoprim, the 4-methoxy group of trimethoprim is replaced with a bromine atom.As trimethoprim, brodimoprim is a selective inhibitor of bacterial dihydrofolate reductase....
, tetroxoprimTetroxoprimTetroxoprim is a derivative of trimethoprim. It was first described in 1979....
, and iclaprimIclaprimIclaprim , codenamed AR-100 and RO-48-2622, is a diaminopyrimidine dihydrofolate reductase inhibitor being developed for the treatment of complicated skin and soft tissue infections caused by antibiotic-resistant bacteria. It is structurally related to trimethoprim...
. - the antimalarial drugs pyrimethaminePyrimethaminePyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
and proguanilProguanilProguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...
. - the experimental new antimalarial drug JPC-2056, which may also be more effective and better tolerated than current treatments against toxoplasmosisToxoplasmosisToxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
. - the chemotherapeuticChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents methotrexateMethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
and pemetrexedPemetrexedPemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of Pleural Mesothelioma as well as non-small cell lung cancer.-History:...
. Methotrexate acts on this enzyme binding to it some 1000 times more tightly than folateFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
itself.