A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of
dihydrofolate reductase
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry ...
, and is a type of
antifolate.
Since folate is needed by rapidly dividing cells to make
thymine
Thymine () ( symbol T or Thy) 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 pyrimidin ...
, this effect may be used to therapeutic advantage. For example,
methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
is used as cancer chemotherapy because it can prevent
neoplastic
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
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.
An extensive review of the chemical space of small-molecules that inhibit DHFR is summarized in
Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline and diaminopyrroloquinazoline, Most of the above specified inhibitors are structural analogues of the substrate dihydrofolate and bind to the active site of the enzyme. Further, it has been recently shown that, in ''E. coli'' DHFR, allosteric site binders can inhibit the enzyme either uncompetitively or non-competitively. The examples provided below are specific molecules belonging to one of the above-mentioned classes.
* the experimental
antimalarial
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young ...
and anti-
toxoplasmosis
Toxoplasmosis is a parasitic disease caused by '' Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or mont ...
compound
JPC-2056
*Oral
piritrexim, a treatment for metastatic urothelial cancer.
*Cycloguanil, a metabolite of
proguanil
Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resista ...
(a component of the oral antimalarial atovaquone-proguanil, or
Malarone
Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommende ...
)
References
*
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