Dihydrofolate reductase inhibitor

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 [4]

Tetrahydrofolate synthesis pathway

Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline and diaminopyrroloquinazoline,[5][6] diaminopyrimidine, diaminopteridine and diaminotriazines.[7] 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[8][9][10]. The examples provided below are specific molecules belonging to one of the above-mentioned classes.

  • the experimental antimalarial and anti-toxoplasmosis compound JPC-2056[11]
  • Oral piritrexim, a treatment for metastatic urothelial cancer.[12]
  • Cycloguanil, a metabolite of proguanil (a component of the oral antimalarial atovaquone-proguanil, or Malarone)

References

  1. ↑ 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.
  2. ↑ McGuire JJ (2003). "Anticancer antifolates: current status and future directions". Current Pharmaceutical Design. 9 (31): 2593–613. doi:10.2174/1381612033453712. PMID 14529544.
  3. ↑ 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.
  4. ↑ Srinivasan B, Tonddast-Navaei S, Roy A, Zhou H, Skolnick J (September 2018). "Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs". Medicinal Research Reviews. doi:10.1002/med.21538. PMID 30192413.
  5. ↑ Srinivasan B, Skolnick J (May 2015). "Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors". The FEBS Journal. 282 (10): 1922–38. doi:10.1111/febs.13244. PMC 4445455. PMID 25703118.
  6. ↑ 9920058, Srinivasan, Bharath; Jeffrey Skolnick & Hongyi Zhou, "United States Patent: 9920058 - Molecules with potent DHFR binding affinity and antibacterial activity", issued March 20, 2018
  7. ↑ Srinivasan B, Tonddast-Navaei S, Skolnick J (October 2015). "Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase". European Journal of Medicinal Chemistry. 103: 600–14. doi:10.1016/j.ejmech.2015.08.021. PMC 4610388. PMID 26414808.
  8. ↑ Srinivasan B, Tonddast-Navaei S, Roy A, Zhou H, Skolnick J (September 2018). "Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs". Medicinal Research Reviews. doi:10.1002/med.21538. PMID 30192413.
  9. ↑ Srinivasan B, Rodrigues JV, Tonddast-Navaei S, Shakhnovich E, Skolnick J (July 2017). "Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants". ACS Chemical Biology. 12 (7): 1848–1857. doi:10.1021/acschembio.7b00175. PMC 5819740. PMID 28525268.
  10. ↑ Srinivasan B, Rodrigues JV, Tonddast-Navaei S, Shakhnovich E, Skolnick J (May 2018). "Correction to Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants". ACS Chemical Biology. 13 (5): 1407. doi:10.1021/acschembio.7b00759. PMID 29688000.
  11. ↑ 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.
  12. ↑ 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.
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