A dihydrofolate reductase inhibitor (DHFR 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.[1][2] Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.[3] An extensive review of the chemical space of small-molecules that inhibit DHFR is summarized in
Tetrahydrofolate synthesis pathway
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.
Oral piritrexim, a treatment for metastatic urothelial cancer.[5]
Cycloguanil, a metabolite of proguanil (a component of the oral antimalarial atovaquone-proguanil, or Malarone), although this has been called into question (see its article)
Referencesedit
^Huennekens FM (1994). "The methotrexate story: a paradigm for development of cancer chemotherapeutic agents". Advances in Enzyme Regulation. 34: 397–419. doi:10.1016/0065-2571(94)90025-6. PMID 7942284.
^McGuire JJ (2003). "Anticancer antifolates: current status and future directions". Current Pharmaceutical Design. 9 (31): 2593–613. doi:10.2174/1381612033453712. PMID 14529544.
^Hawser S, Lociuro S, Islam K (March 2006). "Dihydrofolate reductase inhibitors as antibacterial agents". Biochemical Pharmacology. 71 (7): 941–8. doi:10.1016/j.bcp.2005.10.052. PMID 16359642.
^Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R (March 2008). "Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo". PLOS Neglected Tropical Diseases. 2 (3): e190. doi:10.1371/journal.pntd.0000190. PMC2254147. PMID 18320016.
^de Wit R, Kaye SB, Roberts JT, Stoter G, Scott J, Verweij J (February 1993). "Oral piritrexim, an effective treatment for metastatic urothelial cancer". British Journal of Cancer. 67 (2): 388–90. doi:10.1038/bjc.1993.71. PMC1968166. PMID 8431372.
dihydrofolate, reductase, inhibitor, dihydrofolate, reductase, inhibitor, dhfr, inhibitor, molecule, that, inhibits, function, dihydrofolate, reductase, type, antifolate, since, folate, needed, rapidly, dividing, cells, make, thymine, this, effect, used, thera. A dihydrofolate reductase inhibitor DHFR 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 1 2 Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs host DHFR have found application as antibacterial agents 3 An extensive review of the chemical space of small molecules that inhibit DHFR is summarized in Tetrahydrofolate synthesis pathwayClasses 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 and anti toxoplasmosis compound JPC 2056 4 Oral piritrexim a treatment for metastatic urothelial cancer 5 Cycloguanil a metabolite of proguanil a component of the oral antimalarial atovaquone proguanil or Malarone although this has been called into question see its article References edit Huennekens FM 1994 The methotrexate story a paradigm for development of cancer chemotherapeutic agents Advances in Enzyme Regulation 34 397 419 doi 10 1016 0065 2571 94 90025 6 PMID 7942284 McGuire JJ 2003 Anticancer antifolates current status and future directions Current Pharmaceutical Design 9 31 2593 613 doi 10 2174 1381612033453712 PMID 14529544 Hawser S Lociuro S Islam K March 2006 Dihydrofolate reductase inhibitors as antibacterial agents Biochemical Pharmacology 71 7 941 8 doi 10 1016 j bcp 2005 10 052 PMID 16359642 Mui EJ Schiehser GA Milhous WK Hsu H Roberts CW Kirisits M Muench S Rice D Dubey JP Fowble JW Rathod PK Queener SF Liu SR Jacobus DP McLeod R March 2008 Novel triazine JPC 2067 B inhibits Toxoplasma gondii in vitro and in vivo PLOS Neglected Tropical Diseases 2 3 e190 doi 10 1371 journal pntd 0000190 PMC 2254147 PMID 18320016 de Wit R Kaye SB Roberts JT Stoter G Scott J Verweij J February 1993 Oral piritrexim an effective treatment for metastatic urothelial cancer British Journal of Cancer 67 2 388 90 doi 10 1038 bjc 1993 71 PMC 1968166 PMID 8431372 nbsp This antiinfective drug article is a stub You can help Wikipedia by expanding it vte nbsp This antineoplastic or immunomodulatory drug article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title Dihydrofolate reductase inhibitor amp oldid 1188073010, wikipedia, wiki, book, books, library,
