Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Update on Antifolate Drugs Targets

Author(s): M. P. Costi, S. Ferrari.

Abstract:

Antifolate drugs are molecules directed to interfere with the folate metabolic pathway at some level. They can be recognized among the first rationally designed compounds applying the principle of structural analogy with the substrate developing the antimetabolite strategy. This strategy has taken advantage of the basic different features of the microbial and human folate metabolism and therefore allows targeting the pathway at different steps generating a specificity tools for Medicinal Chemists. Two main problems are giving renewed importance to such targets and therefore improving the efforts to discover new targets in the folate metabolism area. The first one is the increasing resistance to the present drugs due to different mechanisms such as the enzyme modification and the increased production of enzymes with not well recognized importance. The second one is the development of techniques directed to highlight the interference at genetic level of molecular probes as antifolate drug to develop new enzymes previously unknown. This approach is defined as genetic approach to drug discovery, from gene to drugs. The present article describes the importance in drug design and discovery of some antifolate targets among the best known at the present status of research such as thymidylate synthase (TS), dhydrofolate reductases, (DHFR) serine hydroxymethyltransferase (SHMT), folyilpolyglutamyl synthetase (FPGS), g-glutamyl hydrolase (g-GH), glycinamide-ribonucleotide transformylase (GARTfase), amino-imidazole-carboxamide-ribonucleotide transformylase (AICARTfase) and Folate transporters. Discovery, known functions, structure/function studies and inhibition will be described.

Keywords: Antifolate Drugs, thymidylate synthase (TS), dhydrofolate reductases, serine hydroxymethyltransferase (SHMT), folyilpolyglutamyl synthetase (FPGS), glycinamide-ribonucleotide transformylase (GARTfase), THYMIDYLATE SYNTHASE, DIHYDROFOLATE REDUCTASE, Lactobocillus casei, GLUTAMYL HYDROLASE, AMINO-IMIDAZOLECARBOXAMIDE-RIBONUCLEOTIDE FORMYLTRANSFE-RASE, GAR Tfase inhibitors, FOLATE TRANSPORTERS

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Article Details

VOLUME: 2
ISSUE: 2
Year: 2001
Page: [135 - 166]
Pages: 32
DOI: 10.2174/1389450013348669
Price: $58