Targeting DHFR in parasitic protozoa.

Parasitic apicomplexans are responsible for some of the most severe worldwide health problems, including malaria, toxoplasmosis and cryptosporidiosis. These parasites are characterized by a bifunctional enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), which has a crucial role in pyrimidine biosynthesis. Inhibitors of DHFR have been successful in the treatment of toxoplasmosis and malaria. However, there is currently no effective therapy for cryptosporidiosis, and despite early successes against malaria, resistance to DHFR inhibitors in malaria parasites has now become a global problem. Novel DHFR inhibitors, designed using the recently revealed crystal structures of the enzymes from two parasitic protozoa, are in development.

[1]  P. Rathod,et al.  Plasmodium falciparum: kinetic interactions of WR99210 with pyrimethamine-sensitive and pyrimethamine-resistant dihydrofolate reductase. , 1997, Experimental parasitology.

[2]  R. Schilsky,et al.  Antifolates: the next generation. , 1992, Seminars in oncology.

[3]  J. E. Hyde,et al.  Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. , 1997, Molecular and biochemical parasitology.

[4]  C. Plowe,et al.  The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. , 1997, Parasitology today.

[5]  F. Winkler,et al.  Crystal structure of human dihydrofolate reductase complexed with folate. , 1988, European journal of biochemistry.

[6]  C. Inderlied,et al.  New 2,4-diamino-5-(2',5'-substituted benzyl)pyrimidines as potential drugs against opportunistic infections of AIDS and other immune disorders. Synthesis and species-dependent antifolate activity. , 2004, Journal of medicinal chemistry.

[7]  S. Looareesuwan,et al.  Drug resistant malaria, with special reference to Thailand. , 1992, The Southeast Asian journal of tropical medicine and public health.

[8]  D. Warhurst,et al.  Novel alleles of the Plasmodium falciparum dhfr highly resistant to pyrimethamine and chlorcycloguanil, but not WR99210. , 2001, Molecular and biochemical parasitology.

[9]  S. Queener,et al.  Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. , 2004, Journal of medicinal chemistry.

[10]  J. Kublin,et al.  Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial , 2004, The Lancet.

[11]  A. Rosowsky,et al.  Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of Cryptosporidium parvum Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations , 2001, Antimicrobial Agents and Chemotherapy.

[12]  E. Ciszak,et al.  Crystal structure determination at 2.3 A of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-gamma-tetrazole. , 1992, Anti-cancer drug design.

[13]  W G Hol,et al.  Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs. , 2000, Journal of molecular biology.

[14]  W. Sirawaraporn,et al.  Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Guerrant.  Cryptosporidiosis: an emerging, highly infectious threat. , 1997, Emerging infectious diseases.

[16]  C. Plowe,et al.  Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain , 1998, Antimicrobial Agents and Chemotherapy.

[17]  W Pangborn,et al.  Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+. , 2000, Biochemistry.

[18]  T. Flanigan,et al.  Cryptosporidiosis: an unrecognized cause of diarrhea in elderly hospitalized patients. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  S F Queener,et al.  Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase , 1993, Antimicrobial Agents and Chemotherapy.

[20]  R. M. Hyde,et al.  2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 7. Analysis of the effect of 3,5-dialkyl substituent size and shape on binding to four different dihydrofolate reductase enzymes. , 1987, Journal of medicinal chemistry.

[21]  Ping Xu,et al.  Complete Genome Sequence of the Apicomplexan, Cryptosporidium parvum , 2004, Science.

[22]  N. White,et al.  Assessment of the pharmacodynamic properties of antimalarial drugs in vivo , 1997, Antimicrobial agents and chemotherapy.

[23]  Jessica C Kissinger,et al.  Gene transfer in the evolution of parasite nucleotide biosynthesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M Read,et al.  Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria. , 1998, Journal of medicinal chemistry.

[25]  J. Gut,et al.  Potential antifolate resistance determinants and genotypic variation in the bifunctional dihydrofolate reductase-thymidylate synthase gene from human and bovine isolates of Cryptosporidium parvum. , 1996, Molecular and biochemical parasitology.

[26]  Yongyuth Yuthavong,et al.  Insights into antifolate resistance from malarial DHFR-TS structures , 2003, Nature Structural Biology.

[27]  D. Warhurst,et al.  Antimalarial drug discovery: development of inhibitors of dihydrofolate reductase active in drug resistance , 1998 .

[28]  J. E. Hyde,et al.  The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis. , 2002, The Journal of infectious diseases.

[29]  A. Breckenridge,et al.  In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs , 1995, Antimicrobial agents and chemotherapy.

[30]  A. J. Salter,et al.  Trimethoprim-sulfamethoxazole: an assessment of more than 12 years of use. , 1982, Reviews of infectious diseases.

[31]  W. Milhous,et al.  PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists. , 1993, The American journal of tropical medicine and hygiene.

[32]  S. Queener,et al.  Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. , 2003, Journal of medicinal chemistry.

[33]  P K Bryant,et al.  The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution. , 1994, Structure.

[34]  A. Cowman.  Mechanisms of drug resistance in malaria. , 1995, Australian and New Zealand journal of medicine.

[35]  U. Frevert,et al.  Sneaking in through the back entrance: the biology of malaria liver stages. , 2004, Trends in parasitology.

[36]  A. E. Yeo,et al.  Activity of PS-15 and its metabolite, WR99210, against Plasmodium falciparum in an in vivo-in vitro model. , 1996, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[37]  J. Bertino,et al.  Karnofsky memorial lecture. Ode to methotrexate. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  J. E. Hyde,et al.  Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? , 2001, Trends in parasitology.

[39]  Yongyuth Yuthavong,et al.  Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. , 2004, Journal of medicinal chemistry.

[40]  L. Weiss,et al.  Toxoplasma gondii: from animals to humans. , 2000, International journal for parasitology.

[41]  A. Pollak,et al.  Clinical picture. Neonatal signs and symptoms , 2000 .

[42]  D. Roos,et al.  Stable molecular transformation of Toxoplasma gondii: a selectable dihydrofolate reductase-thymidylate synthase marker based on drug-resistance mutations in malaria. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Kublin,et al.  Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study , 2004, BMJ : British Medical Journal.

[44]  Xin Lin,et al.  Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. , 2004, Journal of medicinal chemistry.

[45]  J. P. Davis,et al.  A massive outbreak in Milwaukee of cryptosporidium infection transmitted through the public water supply. , 1994, The New England journal of medicine.

[46]  W. Sirawaraporn,et al.  Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum. , 2000, Journal of medicinal chemistry.

[47]  Bruce R Donald,et al.  Phylogenetic Classification of Protozoa Based on the Structure of the Linker Domain in the Bifunctional Enzyme, Dihydrofolate Reductase-Thymidylate Synthase* , 2003, Journal of Biological Chemistry.

[48]  S J Upton,et al.  Epidemiology of Cryptosporidium: transmission, detection and identification. , 2000, International journal for parasitology.

[49]  Cordell Rl,et al.  Cryptosporidiosis in child care settings: a review of the literature and recommendations for prevention and control. , 1994 .