Targeting Kinetoplastid and Apicomplexan Thymidylate Biosynthesis as an Antiprotozoal Strategy

Author(s): María Valente , Antonio E. Vidal , Dolores González-Pacanowska* .

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 22 , 2019

  Journal Home
Translate in Chinese

Abstract:

Kinetoplastid and apicomplexan parasites comprise a group of protozoans responsible for human diseases, with a serious impact on human health and the socioeconomic growth of developing countries. Chemotherapy is the main option to control these pathogenic organisms and nucleotide metabolism is considered a promising area for the provision of antimicrobial therapeutic targets. Impairment of thymidylate (dTMP) biosynthesis severely diminishes the viability of parasitic protozoa and the absence of enzymatic activities specifically involved in the formation of dTMP (e.g. dUTPase, thymidylate synthase, dihydrofolate reductase or thymidine kinase) results in decreased deoxythymidine triphosphate (dTTP) levels and the so-called thymineless death. In this process, the ratio of deoxyuridine triphosphate (dUTP) versus dTTP in the cellular nucleotide pool has a crucial role. A high dUTP/dTTP ratio leads to uracil misincorporation into DNA, the activation of DNA repair pathways, DNA fragmentation and eventually cell death. The essential character of dTMP synthesis has stimulated interest in the identification and development of drugs that specifically block the biochemical steps involved in thymine nucleotide formation. Here, we review the available literature in relation to drug discovery studies targeting thymidylate biosynthesis in kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp and Toxoplasma gondii) protozoans. The most relevant findings concerning novel inhibitory molecules with antiparasitic activity against these human pathogens are presented herein.

Keywords: Thymidylate biosynthesis, kinetoplastida, apicomplexa, drug target, inhibitor, pyrimidine, dTMP, antiprotozoal.

[1]
Kunz, B.A.; Kohalmi, S.E.; Kunkel, T.A.; Mathews, C.K.; McIntosh, E.M.; Reidy, J.A. International commission for protection against environmental mutagens and carcinogens. Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mutat. Res., 1994, 318(1), 1-64.
[http://dx.doi.org/10.1016/0165-1110(94)90006-X] [PMID: 7519315]
[2]
Reichard, P. Interactions between deoxyribonucleotide and DNA synthesis. Annu. Rev. Biochem., 1988, 57, 349-374.
[http://dx.doi.org/10.1146/annurev.bi.57.070188.002025] [PMID: 3052277]
[3]
Kumar, D.; Abdulovic, A.L.; Viberg, J.; Nilsson, A.K.; Kunkel, T.A.; Chabes, A. Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Res., 2011, 39(4), 1360-1371.
[http://dx.doi.org/10.1093/nar/gkq829] [PMID: 20961955]
[4]
Kunkel, T.A. DNA replication fidelity. J. Biol. Chem., 1992, 267(26), 18251-18254.
[PMID: 1526964]
[5]
Vértessy, B.G.; Tóth, J. Keeping uracil out of DNA: physiological role, structure and catalytic mechanism of dUTPases. Acc. Chem. Res., 2009, 42(1), 97-106.
[http://dx.doi.org/10.1021/ar800114w] [PMID: 18837522]
[6]
Cohen, S.S.; Flaks, J.G.; Barner, H.D.; Loeb, M.R.; Lichtenstein, J. The mode of action of 5-Fluorouracil and its derivatives. Proc. Natl. Acad. Sci. USA, 1958, 44(10), 1004-1012.
[http://dx.doi.org/10.1073/pnas.44.10.1004] [PMID: 16590300]
[7]
WHO. World malaria report, 2017. (Accessed on 15 March, 2015).
[8]
Othman, A.S.; Marin-Mogollon, C.; Salman, A.M.; Franke-Fayard, B.M.; Janse, C.J.; Khan, S.M. The use of transgenic parasites in malaria vaccine research. Expert Rev. Vaccines, 2017, 16(7), 1-13.
[http://dx.doi.org/10.1080/14760584.2017.1333426] [PMID: 28525963]
[9]
Srivastava, S.; Shankar, P.; Mishra, J.; Singh, S. Possibilities and challenges for developing a successful vaccine for leishmaniasis. Parasit. Vectors, 2016, 9(1), 277.
[http://dx.doi.org/10.1186/s13071-016-1553-y] [PMID: 27175732]
[10]
Hassan, H.F.; Coombs, G.H. Purine and pyrimidine metabolism in parasitic protozoa. FEMS Microbiol. Rev., 1988, 4(1), 47-83.
[PMID: 3078769]
[11]
O’Donovan, G.A.; Neuhard, J. Pyrimidine metabolism in microorganisms. Bacteriol. Rev., 1970, 34(3), 278-343.
[PMID: 4919542]
[12]
Zöllner, N. Purine and pyrimidine metabolism. Proc. Nutr. Soc., 1982, 41(3), 329-342.
[http://dx.doi.org/10.1079/PNS19820048] [PMID: 6184723]
[13]
de Koning, H.P.; Bridges, D.J.; Burchmore, R.J. Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy. FEMS Microbiol. Rev., 2005, 29(5), 987-1020.
[http://dx.doi.org/10.1016/j.femsre.2005.03.004] [PMID: 16040150]
[14]
Hammond, D.J.; Gutteridge, W.E. Purine and pyrimidine metabolism in the Trypanosomatidae. Mol. Biochem. Parasitol., 1984, 13(3), 243-261.
[http://dx.doi.org/10.1016/0166-6851(84)90117-8] [PMID: 6396514]
[15]
Hyde, J.E. Targeting purine and pyrimidine metabolism in human apicomplexan parasites. Curr. Drug Targets, 2007, 8(1), 31-47.
[http://dx.doi.org/10.2174/138945007779315524] [PMID: 17266529]
[16]
Ali, J.A.; Creek, D.J.; Burgess, K.; Allison, H.C.; Field, M.C.; Mäser, P.; De Koning, H.P. Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines. Mol. Pharmacol., 2013, 83(2), 439-453.
[http://dx.doi.org/10.1124/mol.112.082321] [PMID: 23188714]
[17]
Valente, M.V.A.E.G.P.D. Potential of pyrimidine metabolism for antitrypanosomal drug discovery, 2016.
[http://dx.doi.org/10.1002/9783527694082.ch6]
[18]
Gao, G.; Nara, T.; Nakajima-Shimada, J.; Aoki, T. Novel organization and sequences of five genes encoding all six enzymes for de novo pyrimidine biosynthesis in Trypanosoma cruzi. J. Mol. Biol., 1999, 285(1), 149-161.
[http://dx.doi.org/10.1006/jmbi.1998.2293] [PMID: 9878395]
[19]
Nara, T.; Hashimoto, M.; Hirawake, H.; Liao, C.W.; Fukai, Y.; Suzuki, S.; Tsubouchi, A.; Morales, J.; Takamiya, S.; Fujimura, T.; Taka, H.; Mineki, R.; Fan, C.K.; Inaoka, D.K.; Inoue, M.; Tanaka, A.; Harada, S.; Kita, K.; Aoki, T. Molecular interaction of the first 3 enzymes of the de novo pyrimidine biosynthetic pathway of Trypanosoma cruzi. Biochem. Biophys. Res. Commun., 2012, 418(1), 140-143.
[http://dx.doi.org/10.1016/j.bbrc.2011.12.148] [PMID: 22245425]
[20]
Hill, B.; Kilsby, J.; McIntosh, R.T.; Wrigglesworth, R.; Ginger, C.D. Pyrimidine biosynthesis in Plasmodium berghei. Int. J. Biochem., 1981, 13(3), 303-310.
[http://dx.doi.org/10.1016/0020-711X(81)90082-3] [PMID: 6260538]
[21]
Krungkrai, J.; Cerami, A.; Henderson, G.B. Pyrimidine biosynthesis in parasitic protozoa: purification of a monofunctional dihydroorotase from Plasmodium berghei and Crithidia fasciculata. Biochemistry, 1990, 29(26), 6270-6275.
[http://dx.doi.org/10.1021/bi00478a023] [PMID: 1976382]
[22]
Arakaki, T.L.; Buckner, F.S.; Gillespie, J.R.; Malmquist, N.A.; Phillips, M.A.; Kalyuzhniy, O.; Luft, J.R.; Detitta, G.T.; Verlinde, C.L.; Van Voorhis, W.C.; Hol, W.G.; Merritt, E.A. Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies. Mol. Microbiol., 2008, 68(1), 37-50.
[http://dx.doi.org/10.1111/j.1365-2958.2008.06131.x] [PMID: 18312275]
[23]
Feliciano, P.R.; Cordeiro, A.T.; Costa-Filho, A.J.; Nonato, M.C. Cloning, expression, purification, and characterization of Leishmania major dihydroorotate dehydrogenase. Protein Expr. Purif., 2006, 48(1), 98-103.
[http://dx.doi.org/10.1016/j.pep.2006.02.010] [PMID: 16600626]
[24]
Takashima, E.; Inaoka, D.K.; Osanai, A.; Nara, T.; Odaka, M.; Aoki, T.; Inaka, K.; Harada, S.; Kita, K. Characterization of the dihydroorotate dehydrogenase as a soluble fumarate reductase in Trypanosoma cruzi. Mol. Biochem. Parasitol., 2002, 122(2), 189-200.
[http://dx.doi.org/10.1016/S0166-6851(02)00100-7] [PMID: 12106873]
[25]
Baldwin, J.; Farajallah, A.M.; Malmquist, N.A.; Rathod, P.K.; Phillips, M.A. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J. Biol. Chem., 2002, 277(44), 41827-41834.
[http://dx.doi.org/10.1074/jbc.M206854200] [PMID: 12189151]
[26]
Hortua Triana, M.A.; Huynh, M.H.; Garavito, M.F.; Fox, B.A.; Bzik, D.J.; Carruthers, V.B.; Löffler, M.; Zimmermann, B.H. Biochemical and molecular characterization of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase from Toxoplasma gondii. Mol. Biochem. Parasitol., 2012, 184(2), 71-81.
[http://dx.doi.org/10.1016/j.molbiopara.2012.04.009] [PMID: 22580100]
[27]
Christopherson, R.I.; Cinquin, O.; Shojaei, M.; Kuehn, D.; Menz, R.I. Cloning and expression of malarial pyrimidine enzymes. Nucleosides Nucleotides Nucleic Acids, 2004, 23(8-9), 1459-1465.
[http://dx.doi.org/10.1081/NCN-200027678] [PMID: 15571277]
[28]
Krungkrai, S.R.; DelFraino, B.J.; Smiley, J.A.; Prapunwattana, P.; Mitamura, T.; Horii, T.; Krungkrai, J. A novel enzyme complex of orotate phosphoribosyltransferase and orotidine 5′-monophosphate decarboxylase in human malaria parasite Plasmodium falciparum: physical association, kinetics, and inhibition characterization. Biochemistry, 2005, 44(5), 1643-1652.
[http://dx.doi.org/10.1021/bi048439h] [PMID: 15683248]
[29]
Krungkrai, S.R.; Prapunwattana, P.; Horii, T.; Krungkrai, J. Orotate phosphoribosyltransferase and orotidine 5′-monophosphate decarboxylase exist as multienzyme complex in human malaria parasite Plasmodium falciparum. Biochem. Biophys. Res. Commun., 2004, 318(4), 1012-1018.
[http://dx.doi.org/10.1016/j.bbrc.2004.04.124] [PMID: 15147974]
[30]
Carter, D.; Donald, R.G.; Roos, D.; Ullman, B. Expression, purification, and characterization of uracil phosphoribosyltransferase from Toxoplasma gondii. Mol. Biochem. Parasitol., 1997, 87(2), 137-144.
[http://dx.doi.org/10.1016/S0166-6851(97)00058-3] [PMID: 9247925]
[31]
Hammond, D.J.; Gutteridge, W.E. UMP synthesis in the kinetoplastida. Biochim. Biophys. Acta, 1982, 718(1), 1-10.
[http://dx.doi.org/10.1016/0304-4165(82)90002-2] [PMID: 6753942]
[32]
Srivastava, A.; Creek, D.J.; Evans, K.J.; De Souza, D.; Schofield, L.; Müller, S.; Barrett, M.P.; McConville, M.J.; Waters, A.P. Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites. PLoS Pathog., 2015, 11(6)e1004882
[http://dx.doi.org/10.1371/journal.ppat.1004882] [PMID: 26042734]
[33]
Creek, D.J.; Mazet, M.; Achcar, F.; Anderson, J.; Kim, D.H.; Kamour, R.; Morand, P.; Millerioux, Y.; Biran, M.; Kerkhoven, E.J.; Chokkathukalam, A.; Weidt, S.K.; Burgess, K.E.; Breitling, R.; Watson, D.G.; Bringaud, F.; Barrett, M.P. Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose. PLoS Pathog., 2015, 11(3)e1004689
[http://dx.doi.org/10.1371/journal.ppat.1004689] [PMID: 25775470]
[34]
Valente, M.; Timm, J.; Castillo-Acosta, V.M.; Ruiz-Pérez, L.M.; Balzarini, T.; Nettleship, J.E.; Bird, L.E.; Rada, H.; Wilson, K.S.; González-Pacanowska, D. Cell cycle regulation and novel structural features of thymidine kinase, an essential enzyme in Trypanosoma brucei. Mol. Microbiol., 2016, 102(3), 365-385.
[http://dx.doi.org/10.1111/mmi.13467] [PMID: 27426054]
[35]
Leija, C.; Rijo-Ferreira, F.; Kinch, L.N.; Grishin, N.V.; Nischan, N.; Kohler, J.J.; Hu, Z.; Phillips, M.A. Pyrimidine salvage enzymes are essential for de novo biosynthesis of deoxypyrimidine nucleotides in Trypanosoma brucei. PLoS Pathog., 2016, 12(11)e1006010
[http://dx.doi.org/10.1371/journal.ppat.1006010] [PMID: 27820863]
[36]
Mosbaugh, D.W.; Bennett, S.E. Uracil-excision DNA repair. Prog. Nucleic Acid Res. Mol. Biol., 1994, 48, 315-370.
[http://dx.doi.org/10.1016/S0079-6603(08)60859-4] [PMID: 7938553]
[37]
Auerbach, P.; Bennett, R.A.; Bailey, E.A.; Krokan, H.E.; Demple, B. Mutagenic specificity of endogenously generated abasic sites in Saccharomyces cerevisiae chromosomal DNA. Proc. Natl. Acad. Sci. USA, 2005, 102(49), 17711-17716.
[http://dx.doi.org/10.1073/pnas.0504643102] [PMID: 16314579]
[38]
Blount, B.C.; Mack, M.M.; Wehr, C.M.; MacGregor, J.T.; Hiatt, R.A.; Wang, G.; Wickramasinghe, S.N.; Everson, R.B.; Ames, B.N. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA, 1997, 94(7), 3290-3295.
[http://dx.doi.org/10.1073/pnas.94.7.3290] [PMID: 9096386]
[39]
Duthie, S.J.; Narayanan, S.; Sharp, L.; Little, J.; Basten, G.; Powers, H. Folate, DNA stability and colo-rectal neoplasia. Proc. Nutr. Soc., 2004, 63(4), 571-578.
[http://dx.doi.org/10.1079/PNS2004] [PMID: 15831129]
[40]
Ahmad, S.I.; Kirk, S.H.; Eisenstark, A. Thymine metabolism and thymineless death in prokaryotes and eukaryotes. Annu. Rev. Microbiol., 1998, 52, 591-625.
[http://dx.doi.org/10.1146/annurev.micro.52.1.591] [PMID: 9891809]
[41]
Fenech, M. Recommended dietary allowances (RDAs) for genomic stability. Mutat. Res., 2001, 480-481, 51-54.
[http://dx.doi.org/10.1016/S0027-5107(01)00168-3] [PMID: 11506798]
[42]
Quesada-Soriano, I.; Casas-Solvas, J.M.; Recio, E.; Ruiz-Pérez, L.M.; Vargas-Berenguel, A.; González-Pacanowska, D.; García-Fuentes, L. Kinetic properties and specificity of trimeric Plasmodium falciparum and human dUTPases. Biochimie, 2010, 92(2), 178-186.
[http://dx.doi.org/10.1016/j.biochi.2009.10.008] [PMID: 19879316]
[43]
Cedergren-Zeppezauer, E.S.; Larsson, G.; Nyman, P.O.; Dauter, Z.; Wilson, K.S. Crystal structure of a dUTPase. Nature, 1992, 355(6362), 740-743.
[http://dx.doi.org/10.1038/355740a0] [PMID: 1311056]
[44]
Whittingham, J.L.; Leal, I.; Nguyen, C.; Kasinathan, G.; Bell, E.; Jones, A.F.; Berry, C.; Benito, A.; Turkenburg, J.P.; Dodson, E.J.; Ruiz Perez, L.M.; Wilkinson, A.J.; Johansson, N.G.; Brun, R.; Gilbert, I.H.; Gonzalez Pacanowska, D.; Wilson, K.S. dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors. Structure, 2005, 13(2), 329-338.
[http://dx.doi.org/10.1016/j.str.2004.11.015] [PMID: 15698576]
[45]
Tarbouriech, N.; Buisson, M.; Seigneurin, J.M.; Cusack, S.; Burmeister, W.P. The monomeric dUTPase from Epstein-Barr virus mimics trimeric dUTPases. Structure, 2005, 13(9), 1299-1310.
[http://dx.doi.org/10.1016/j.str.2005.06.009] [PMID: 16154087]
[46]
Bernier-Villamor, V.; Camacho, A.; Hidalgo-Zarco, F.; Pérez, J.; Ruiz-Pérez, L.M.; González-Pacanowska, D. Characterization of deoxyuridine 5′-triphosphate nucleotidohydrolase from Trypanosoma cruzi. FEBS Lett., 2002, 526(1-3), 147-150.
[http://dx.doi.org/10.1016/S0014-5793(02)03158-7] [PMID: 12208522]
[47]
Berriman, M.; Ghedin, E.; Hertz-Fowler, C.; Blandin, G.; Renauld, H.; Bartholomeu, D.C.; Lennard, N.J.; Caler, E.; Hamlin, N.E.; Haas, B.; Böhme, U.; Hannick, L.; Aslett, M.A.; Shallom, J.; Marcello, L.; Hou, L.; Wickstead, B.; Alsmark, U.C.; Arrowsmith, C.; Atkin, R.J.; Barron, A.J.; Bringaud, F.; Brooks, K.; Carrington, M.; Cherevach, I.; Chillingworth, T.J.; Churcher, C.; Clark, L.N.; Corton, C.H.; Cronin, A.; Davies, R.M.; Doggett, J.; Djikeng, A.; Feldblyum, T.; Field, M.C.; Fraser, A.; Goodhead, I.; Hance, Z.; Harper, D.; Harris, B.R.; Hauser, H.; Hostetler, J.; Ivens, A.; Jagels, K.; Johnson, D.; Johnson, J.; Jones, K.; Kerhornou, A.X.; Koo, H.; Larke, N.; Landfear, S.; Larkin, C.; Leech, V.; Line, A.; Lord, A.; Macleod, A.; Mooney, P.J.; Moule, S.; Martin, D.M.; Morgan, G.W.; Mungall, K.; Norbertczak, H.; Ormond, D.; Pai, G.; Peacock, C.S.; Peterson, J.; Quail, M.A.; Rabbinowitsch, E.; Rajandream, M.A.; Reitter, C.; Salzberg, S.L.; Sanders, M.; Schobel, S.; Sharp, S.; Simmonds, M.; Simpson, A.J.; Tallon, L.; Turner, C.M.; Tait, A.; Tivey, A.R.; Van Aken, S.; Walker, D.; Wanless, D.; Wang, S.; White, B.; White, O.; Whitehead, S.; Woodward, J.; Wortman, J.; Adams, M.D.; Embley, T.M.; Gull, K.; Ullu, E.; Barry, J.D.; Fairlamb, A.H.; Opperdoes, F.; Barrell, B.G.; Donelson, J.E.; Hall, N.; Fraser, C.M.; Melville, S.E.; El-Sayed, N.M. The genome of the African trypanosome Trypanosoma brucei. Science, 2005, 309(5733), 416-422.
[http://dx.doi.org/10.1126/science.1112642] [PMID: 16020726]
[48]
Camacho, A.; Hidalgo-Zarco, F.; Bernier-Villamor, V.; Ruiz-Pérez, L.M.; González-Pacanowska, D. Properties of Leishmania major dUTP nucleotidohydrolase, a distinct nucleotide-hydrolysing enzyme in kinetoplastids. Biochem. J., 2000, 346(Pt 1), 163-168.
[http://dx.doi.org/10.1042/bj3460163] [PMID: 10657253]
[49]
Harkiolaki, M.; Dodson, E.J.; Bernier-Villamor, V.; Turkenburg, J.P.; González-Pacanowska, D.; Wilson, K.S. The crystal structure of Trypanosoma cruzi dUTPase reveals a novel dUTP/dUDP binding fold. Structure, 2004, 12(1), 41-53.
[http://dx.doi.org/10.1016/j.str.2003.11.016] [PMID: 14725764]
[50]
Hidalgo-Zarco, F.; Camacho, A.G.; Bernier-Villamor, V.; Nord, J.; Ruiz-Perez, L.M.; Gonzalez-Pacanowska, D. Kinetic properties and inhibition of the dimeric dUTPase-dUDPase from Leishmania major. Protein Sci., 2001, 10, 1426-1433.
[51]
Castillo-Acosta, V.M.; Estévez, A.M.; Vidal, A.E.; Ruiz-Perez, L.M.; González-Pacanowska, D. Depletion of dimeric all-alpha dUTPase induces DNA strand breaks and impairs cell cycle progression in Trypanosoma brucei. Int. J. Biochem. Cell Biol., 2008, 40(12), 2901-2913.
[http://dx.doi.org/10.1016/j.biocel.2008.06.009] [PMID: 18656547]
[52]
Castillo-Acosta, V.M.; Aguilar-Pereyra, F.; García-Caballero, D.; Vidal, A.E.; Ruiz-Pérez, L.M.; González-Pacanowska, D. Pyrimidine requirements in deoxyuridine triphosphate nucleotidohydrolase deficient Trypanosoma brucei mutants. Mol. Biochem. Parasitol., 2013, 187(1), 9-13.
[http://dx.doi.org/10.1016/j.molbiopara.2012.11.003] [PMID: 23201394]
[53]
Larsson, G.; Nyman, P.O.; Kvassman, J.O. Kinetic characterization of dUTPase from Escherichia coli. J. Biol. Chem., 1996, 271(39), 24010-24016.
[http://dx.doi.org/10.1074/jbc.271.39.24010] [PMID: 8798636]
[54]
Nguyen, C.; Kasinathan, G.; Leal-Cortijo, I.; Musso-Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-Pérez, L.M.; Johansson, N.G.; González-Pacanowska, D.; Gilbert, I.H. Deoxyuridine triphosphate nucleotidohydrolase as a potential antiparasitic drug target. J. Med. Chem., 2005, 48(19), 5942-5954.
[http://dx.doi.org/10.1021/jm050111e] [PMID: 16161998]
[55]
Moroz, O.V.; Murzin, A.G.; Makarova, K.S.; Koonin, E.V.; Wilson, K.S.; Galperin, M.Y. Dimeric dUTPases, HisE, and MazG belong to a new superfamily of all-alpha NTP pyrophosphohydrolases with potential “house-cleaning” functions. J. Mol. Biol., 2005, 347(2), 243-255.
[http://dx.doi.org/10.1016/j.jmb.2005.01.030] [PMID: 15740738]
[56]
Mc Carthy, O.K.; Schipani, A.; Buendía, A.M.; Ruiz-Perez, L.M.; Kaiser, M.; Brun, R.; Pacanowska, D.G.; Gilbert, I.H. Design, synthesis and evaluation of novel uracil amino acid conjugates for the inhibition of Trypanosoma cruzi dUTPase. Bioorg. Med. Chem. Lett., 2006, 16(14), 3809-3812.
[http://dx.doi.org/10.1016/j.bmcl.2006.04.027] [PMID: 16677813]
[57]
Hemsworth, G.R.; González-Pacanowska, D.; Wilson, K.S. On the catalytic mechanism of dimeric dUTPases. Biochem. J., 2013, 456(1), 81-88.
[http://dx.doi.org/10.1042/BJ20130796] [PMID: 24001052]
[58]
Hemsworth, G.R.; Moroz, O.V.; Fogg, M.J.; Scott, B.; Bosch-Navarrete, C.; González-Pacanowska, D.; Wilson, K.S. The crystal structure of the Leishmania major deoxyuridine triphosphate nucleotidohydrolase in complex with nucleotide analogues, dUMP, and deoxyuridine. J. Biol. Chem., 2011, 286(18), 16470-16481.
[http://dx.doi.org/10.1074/jbc.M111.224873] [PMID: 21454646]
[59]
Brocchieri, L. Low-complexity regions in Plasmodium proteins: in search of a function. Genome Res., 2001, 11(2), 195-197.
[http://dx.doi.org/10.1101/gr.176401] [PMID: 11157782]
[60]
Recio, E.; Musso-Buendía, A.; Vidal, A.E.; Ruda, G.F.; Kasinathan, G.; Nguyen, C.; Ruiz-Pérez, L.M.; Gilbert, I.H.; González-Pacanowska, D. Site-directed mutagenesis provides insights into the selective binding of trityl derivatives to Plasmodium falciparum dUTPase. Eur. J. Med. Chem., 2011, 46(8), 3309-3314.
[http://dx.doi.org/10.1016/j.ejmech.2011.04.052] [PMID: 21600680]
[61]
Nguyen, C.; Ruda, G.F.; Schipani, A.; Kasinathan, G.; Leal, I.; Musso-Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-Pérez, L.M.; Sahlberg, B.L.; Johansson, N.G.; Gonzalez-Pacanowska, D.; Gilbert, I.H. Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. J. Med. Chem., 2006, 49(14), 4183-4195.
[http://dx.doi.org/10.1021/jm060126s] [PMID: 16821778]
[62]
McCarthy, O.; Musso-Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-Perez, L.M.; Johansson, N.G.; Pacanowska, D.G.; Gilbert, I.H. Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase. Eur. J. Med. Chem., 2009, 44(2), 678-688.
[http://dx.doi.org/10.1016/j.ejmech.2008.05.018] [PMID: 18619713]
[63]
Ruda, G.F.; Nguyen, C.; Ziemkowski, P.; Felczak, K.; Kasinathan, G.; Musso-Buendia, A.; Sund, C.; Zhou, X.X.; Kaiser, M.; Ruiz-Pérez, L.M.; Brun, R.; Kulikowski, T.; Johansson, N.G.; González-Pacanowska, D.; Gilbert, I.H. Modified 5′-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase. ChemMedChem, 2011, 6(2), 309-320.
[http://dx.doi.org/10.1002/cmdc.201000445] [PMID: 21246738]
[64]
Baragaña, B.; McCarthy, O.; Sánchez, P.; Bosch-Navarrete, C.; Kaiser, M.; Brun, R.; Whittingham, J.L.; Roberts, S.M.; Zhou, X.X.; Wilson, K.S.; Johansson, N.G.; González-Pacanowska, D.; Gilbert, I.H. β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. Bioorg. Med. Chem., 2011, 19(7), 2378-2391.
[http://dx.doi.org/10.1016/j.bmc.2011.02.012] [PMID: 21411327]
[65]
Hampton, S.E.; Baragaña, B.; Schipani, A.; Bosch-Navarrete, C.; Musso-Buendía, J.A.; Recio, E.; Kaiser, M.; Whittingham, J.L.; Roberts, S.M.; Shevtsov, M.; Brannigan, J.A.; Kahnberg, P.; Brun, R.; Wilson, K.S.; González-Pacanowska, D.; Johansson, N.G.; Gilbert, I.H. Design, synthesis, and evaluation of 5′-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase. ChemMedChem, 2011, 6(10), 1816-1831.
[http://dx.doi.org/10.1002/cmdc.201100255] [PMID: 22049550]
[66]
Hampton, S.E.; Schipani, A.; Bosch-Navarrete, C.; Recio, E.; Kaiser, M.; Kahnberg, P.; González-Pacanowska, D.; Johansson, N.G.; Gilbert, I.H. Investigation of acyclic uridine amide and 5′-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase. Bioorg. Med. Chem., 2013, 21(18), 5876-5885.
[http://dx.doi.org/10.1016/j.bmc.2013.07.004] [PMID: 23916149]
[67]
Rodolfo André de Araújo Santos, C.A.B.; Jahan, B. Ghasemi, R.S.-S.; Barbosa, E.G. Mixed 2D–3D-LQTA-QSAR study of a series of Plasmodium falciparum dUTPase inhibitors. Med. Chem. Res., 2015, 2015, 1098-1111.
[http://dx.doi.org/10.1007/s00044-014-1189-4]
[68]
Ivanetich, K.M.; Santi, D.V. Thymidylate synthase-dihydrofolate reductase in protozoa. Exp. Parasitol., 1990, 70(3), 367-371.
[http://dx.doi.org/10.1016/0014-4894(90)90119-W] [PMID: 2178951]
[69]
Amyes, S.G.; Smith, J.T. Trimethoprim action and its analogy with thymine starvation. Antimicrob. Agents Chemother., 1974, 5(2), 169-178.
[http://dx.doi.org/10.1128/AAC.5.2.169] [PMID: 4275615]
[70]
Khodursky, A.; Guzmán, E.C.; Hanawalt, P.C. Thymineless Death Lives On: New insights into a classic phenomenon. Annu. Rev. Microbiol., 2015, 69, 247-263.
[http://dx.doi.org/10.1146/annurev-micro-092412-155749] [PMID: 26253395]
[71]
Grumont, R.; Sirawaraporn, W.; Santi, D.V. Heterologous expression of the bifunctional thymidylate synthase-dihydrofolate reductase from Leishmania major. Biochemistry, 1988, 27(10), 3776-3784.
[http://dx.doi.org/10.1021/bi00410a039] [PMID: 2841973]
[72]
Reche, P.; Arrebola, R.; Olmo, A.; Santi, D.V.; Gonzalez-Pacanowska, D.; Ruiz-Perez, L.M. Cloning and expression of the dihydrofolate reductase-thymidylate synthase gene from Trypanosoma cruzi. Mol. Biochem. Parasitol., 1994, 65(2), 247-258.
[http://dx.doi.org/10.1016/0166-6851(94)90076-0] [PMID: 7969266]
[73]
Gamarro, F.; Yu, P.L.; Zhao, J.; Edman, U.; Greene, P.J.; Santi, D. Trypanosoma brucei dihydrofolate reductase-thymidylate synthase: gene isolation and expression and characterization of the enzyme. Mol. Biochem. Parasitol., 1995, 72(1-2), 11-22.
[http://dx.doi.org/10.1016/0166-6851(95)00059-A] [PMID: 8538681]
[74]
Cruz, A.; Coburn, C.M.; Beverley, S.M. Double targeted gene replacement for creating null mutants. Proc. Natl. Acad. Sci. USA, 1991, 88(16), 7170-7174.
[http://dx.doi.org/10.1073/pnas.88.16.7170] [PMID: 1651496]
[75]
Sienkiewicz, N.; Jarosławski, S.; Wyllie, S.; Fairlamb, A.H. Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes. Mol. Microbiol., 2008, 69(2), 520-533.
[http://dx.doi.org/10.1111/j.1365-2958.2008.06305.x] [PMID: 18557814]
[76]
Zuccotto, F.; Brun, R.; Gonzalez Pacanowska, D.; Ruiz Perez, L.M.; Gilbert, I.H. The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg. Med. Chem. Lett., 1999, 9(10), 1463-1468.
[http://dx.doi.org/10.1016/S0960-894X(99)00213-9] [PMID: 10360757]
[77]
Scott, D.A.; Coombs, G.H.; Sanderson, B.E. Effects of methotrexate and other antifolates on the growth and dihydrofolate reductase activity of Leishmania promastigotes. Biochem. Pharmacol., 1987, 36(12), 2043-2045.
[http://dx.doi.org/10.1016/0006-2952(87)90508-9] [PMID: 3593407]
[78]
Barrett, M.P.; Gilbert, I.H. Perspectives for new drugs against trypanosomiasis and leishmaniasis. Curr. Top. Med. Chem., 2002, 2(5), 471-482.
[http://dx.doi.org/10.2174/1568026024607427] [PMID: 11966468]
[79]
Gilbert, I.H. Inhibitors of dihydrofolate reductase in Leishmania and trypanosomes. Biochim. Biophys. Acta, 2002, 1587(2-3), 249-257.
[http://dx.doi.org/10.1016/S0925-4439(02)00088-1] [PMID: 12084467]
[80]
Knighton, D.R.; Kan, C.C.; Howland, E.; Janson, C.A.; Hostomska, Z.; Welsh, K.M.; Matthews, D.A. Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase. Nat. Struct. Biol., 1994, 1(3), 186-194.
[http://dx.doi.org/10.1038/nsb0394-186] [PMID: 7656037]
[81]
Chowdhury, S.F.; Di Lucrezia, R.; Guerrero, R.H.; Brun, R.; Goodman, J.; Ruiz-Perez, L.M.; Pacanowska, D.G.; Gilbert, I.H. Novel inhibitors of Leishmanial dihydrofolate reductase. Bioorg. Med. Chem. Lett., 2001, 11(8), 977-980.
[http://dx.doi.org/10.1016/S0960-894X(01)00089-0] [PMID: 11327604]
[82]
Zuccotto, F.; Zvelebil, M.; Brun, R.; Chowdhury, S.F.; Di Lucrezia, R.; Leal, I.; Maes, L.; Ruiz-Perez, L.M.; Gonzalez Pacanowska, D.; Gilbert, I.H. Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase. Eur. J. Med. Chem., 2001, 36(5), 395-405.
[http://dx.doi.org/10.1016/S0223-5234(01)01235-1] [PMID: 11451529]
[83]
Atreya, C.E.; Johnson, E.F.; Irwin, J.J.; Dow, A.; Massimine, K.M.; Coppens, I.; Stempliuk, V.; Beverley, S.; Joiner, K.A.; Shoichet, B.K.; Anderson, K.S. A molecular docking strategy identifies Eosin B as a non-active site inhibitor of protozoal bifunctional thymidylate synthase-dihydrofolate reductase. J. Biol. Chem., 2003, 278(16), 14092-14100.
[http://dx.doi.org/10.1074/jbc.M212690200] [PMID: 12556445]
[84]
McGuire, J.J. Anticancer antifolates: current status and future directions. Curr. Pharm. Des., 2003, 9(31), 2593-2613.
[http://dx.doi.org/10.2174/1381612033453712] [PMID: 14529544]
[85]
Senkovich, O.; Bhatia, V.; Garg, N.; Chattopadhyay, D. Lipophilic antifolate trimetrexate is a potent inhibitor of Trypanosoma cruzi: prospect for chemotherapy of Chagas’ disease. Antimicrob. Agents Chemother., 2005, 49(8), 3234-3238.
[http://dx.doi.org/10.1128/AAC.49.8.3234-3238.2005] [PMID: 16048931]
[86]
Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D. Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function. Proteins, 2008, 73(4), 889-901.
[http://dx.doi.org/10.1002/prot.22115] [PMID: 18536013]
[87]
Senkovich, O.; Schormann, N.; Chattopadhyay, D. Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate. Acta Crystallogr. D Biol. Crystallogr., 2009, 65(Pt 7), 704-716.
[http://dx.doi.org/10.1107/S090744490901230X] [PMID: 19564691]
[88]
Schormann, N.; Velu, S.E.; Murugesan, S.; Senkovich, O.; Walker, K.; Chenna, B.C.; Shinkre, B.; Desai, A.; Chattopadhyay, D. Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg. Med. Chem., 2010, 18(11), 4056-4066.
[http://dx.doi.org/10.1016/j.bmc.2010.04.020] [PMID: 20452776]
[89]
Fonseca-Berzal, C.; Rojas Ruiz, F.A.; Escario, J.A.; Kouznetsov, V.V.; Gómez-Barrio, A. In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents. Bioorg. Med. Chem. Lett., 2014, 24(4), 1209-1213.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.071] [PMID: 24461296]
[90]
Nefertiti, A.S.G.; Batista, M.M.; Da Silva, P.B.; Batista, D.G.J.; Da Silva, C.F.; Peres, R.B.; Torres-Santos, E.C.; Cunha-Junior, E.F.; Holt, E.; Boykin, D.W.; Brun, R.; Wenzler, T.; Soeiro, M.N.C. In vitro and in vivo studies of the trypanocidal effect of novel quinolines. Antimicrob. Agents Chemother., 2018, 62(2), 62.
[PMID: 29203485]
[91]
Konstantinović, J.; Videnović, M.; Orsini, S.; Bogojević, K.; D’Alessandro, S.; Scaccabarozzi, D.; Terzić Jovanović, N.; Gradoni, L.; Basilico, N.; Šolaja, B.A. Novel aminoquinoline derivatives significantly reduce parasite load in Leishmania infantum Infected Mice. ACS Med. Chem. Lett., 2018, 9(7), 629-634.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00053] [PMID: 30034591]
[92]
Sahu, N.P.; Pal, C.; Mandal, N.B.; Banerjee, S.; Raha, M.; Kundu, A.P.; Basu, A.; Ghosh, M.; Roy, K.; Bandyopadhyay, S. Synthesis of a novel quinoline derivative, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide--a potential antileishmanial agent. Bioorg. Med. Chem., 2002, 10(6), 1687-1693.
[http://dx.doi.org/10.1016/S0968-0896(02)00046-9] [PMID: 11937327]
[93]
Palit, P.; Hazra, A.; Maity, A.; Vijayan, R.S.; Manoharan, P.; Banerjee, S.; Mondal, N.B.; Ghoshal, N.; Ali, N. Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis. Antimicrob. Agents Chemother., 2012, 56(1), 432-445.
[http://dx.doi.org/10.1128/AAC.00700-11] [PMID: 22024817]
[94]
Bello, A.R.; Nare, B.; Freedman, D.; Hardy, L.; Beverley, S.M. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc. Natl. Acad. Sci. USA, 1994, 91(24), 11442-11446.
[http://dx.doi.org/10.1073/pnas.91.24.11442] [PMID: 7972081]
[95]
Cunningham, M.L.; Beverley, S.M. Pteridine salvage throughout the Leishmania infectious cycle: implications for antifolate chemotherapy. Mol. Biochem. Parasitol., 2001, 113(2), 199-213.
[http://dx.doi.org/10.1016/S0166-6851(01)00213-4] [PMID: 11295174]
[96]
Nare, B.; Hardy, L.W.; Beverley, S.M. The roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. J. Biol. Chem., 1997, 272(21), 13883-13891.
[http://dx.doi.org/10.1074/jbc.272.21.13883] [PMID: 9153248]
[97]
Tulloch, L.B.; Martini, V.P.; Iulek, J.; Huggan, J.K.; Lee, J.H.; Gibson, C.L.; Smith, T.K.; Suckling, C.J.; Hunter, W.N. Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. J. Med. Chem., 2010, 53(1), 221-229.
[http://dx.doi.org/10.1021/jm901059x] [PMID: 19916554]
[98]
Cavazzuti, A.; Paglietti, G.; Hunter, W.N.; Gamarro, F.; Piras, S.; Loriga, M.; Allecca, S.; Corona, P.; McLuskey, K.; Tulloch, L.; Gibellini, F.; Ferrari, S.; Costi, M.P. Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. Proc. Natl. Acad. Sci. USA, 2008, 105(5), 1448-1453.
[http://dx.doi.org/10.1073/pnas.0704384105] [PMID: 18245389]
[99]
Hardy, L.W.; Matthews, W.; Nare, B.; Beverley, S.M. Biochemical and genetic tests for inhibitors of leishmania pteridine pathways. Exp. Parasitol., 1997, 87(3), 158-170.
[http://dx.doi.org/10.1006/expr.1997.4207] [PMID: 9398595]
[100]
Kaur, J.; Kumar, P.; Tyagi, S.; Pathak, R.; Batra, S.; Singh, P.; Singh, N. In silico screening, structure-activity relationship, and biologic evaluation of selective pteridine reductase inhibitors targeting visceral leishmaniasis. Antimicrob. Agents Chemother., 2011, 55(2), 659-666.
[http://dx.doi.org/10.1128/AAC.00436-10] [PMID: 21115787]
[101]
Kumar, P.; Kumar, A.; Verma, S.S.; Dwivedi, N.; Singh, N.; Siddiqi, M.I.; Tripathi, R.P.; Dube, A.; Singh, N. Leishmania donovani pteridine reductase 1: biochemical properties and structure-modeling studies. Exp. Parasitol., 2008, 120(1), 73-79.
[http://dx.doi.org/10.1016/j.exppara.2008.05.005] [PMID: 18617167]
[102]
Pandey, V.P.; Bisht, S.S.; Mishra, M.; Kumar, A.; Siddiqi, M.I.; Verma, A.; Mittal, M.; Sane, S.A.; Gupta, S.; Tripathi, R.P. Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents. Eur. J. Med. Chem., 2010, 45(6), 2381-2388.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.018] [PMID: 20199824]
[103]
Ferrari, S.; Morandi, F.; Motiejunas, D.; Nerini, E.; Henrich, S.; Luciani, R.; Venturelli, A.; Lazzari, S.; Calò, S.; Gupta, S.; Hannaert, V.; Michels, P.A.; Wade, R.C.; Costi, M.P. Virtual screening identification of nonfolate compounds, including a CNS drug, as antiparasitic agents inhibiting pteridine reductase. J. Med. Chem., 2011, 54(1), 211-221.
[http://dx.doi.org/10.1021/jm1010572] [PMID: 21126022]
[104]
Mpamhanga, C.P.; Spinks, D.; Tulloch, L.B.; Shanks, E.J.; Robinson, D.A.; Collie, I.T.; Fairlamb, A.H.; Wyatt, P.G.; Frearson, J.A.; Hunter, W.N.; Gilbert, I.H.; Brenk, R. One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J. Med. Chem., 2009, 52(14), 4454-4465.
[http://dx.doi.org/10.1021/jm900414x] [PMID: 19527033]
[105]
Dawson, A.; Gibellini, F.; Sienkiewicz, N.; Tulloch, L.B.; Fyfe, P.K.; McLuskey, K.; Fairlamb, A.H.; Hunter, W.N. Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate. Mol. Microbiol., 2006, 61(6), 1457-1468.
[http://dx.doi.org/10.1111/j.1365-2958.2006.05332.x] [PMID: 16968221]
[106]
Chandrasekaran, S.; Dayakar, A.; Veronica, J.; Sundar, S.; Maurya, R. An in vitro study of apoptotic like death in Leishmania donovani promastigotes by withanolides. Parasitol. Int., 2013, 62(3), 253-261.
[http://dx.doi.org/10.1016/j.parint.2013.01.007] [PMID: 23416156]
[107]
Chandrasekaran, S.; Veronica, J.; Gundampati, R.K.; Sundar, S.; Maurya, R. Exploring the inhibitory activity of Withaferin-A against Pteridine reductase-1 of L. donovani. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1029-1037.
[http://dx.doi.org/10.3109/14756366.2015.1088841] [PMID: 26406482]
[108]
Vadloori, B.; Sharath, A.K.; Prabhu, N.P.; Maurya, R. Homology modelling, molecular docking, and molecular dynamics simulations reveal the inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase enzyme by Withaferin-A. BMC Res. Notes, 2018, 11(1), 246.
[http://dx.doi.org/10.1186/s13104-018-3354-1] [PMID: 29661206]
[109]
Ranjbarian, F.; Vodnala, M.; Vodnala, S.M.; Rofougaran, R.; Thelander, L.; Hofer, A. Trypanosoma brucei thymidine kinase is tandem protein consisting of two homologous parts, which together enable efficient substrate binding. J. Biol. Chem., 2012, 287(21), 17628-17636.
[http://dx.doi.org/10.1074/jbc.M112.340059] [PMID: 22442154]
[110]
Timm, J.; Bosch-Navarrete, C.; Recio, E.; Nettleship, J.E.; Rada, H.; González-Pacanowska, D.; Wilson, K.S. Structural and kinetic characterization of thymidine kinase from Leishmania major. PLoS Negl. Trop. Dis., 2015, 9(5)e0003781
[http://dx.doi.org/10.1371/journal.pntd.0003781] [PMID: 25978379]
[111]
Nyiri, K.; Vertessy, B.G. Perturbation of genome integrity to fight pathogenic microorganisms. Biochim. Biophys. Acta, 2016.
[PMID: 27217086]
[112]
Pearson, R.D.; Hewlett, E.L. Use of pyrimethamine-sulfadoxine (Fansidar) in prophylaxis against chloroquine-resistant Plasmodium falciparum and Pneumocystis carinii. Ann. Intern. Med., 1987, 106(5), 714-718.
[http://dx.doi.org/10.7326/0003-4819-106-5-714] [PMID: 3551713]
[113]
Patel, S.N.; Kain, K.C. Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev. Anti Infect. Ther., 2005, 3(6), 849-861.
[http://dx.doi.org/10.1586/14787210.3.6.849] [PMID: 16307498]
[114]
Takala-Harrison, S.; Laufer, M.K. Antimalarial drug resistance in Africa: key lessons for the future. Ann. N. Y. Acad. Sci., 2015, 1342, 62-67.
[http://dx.doi.org/10.1111/nyas.12766] [PMID: 25891142]
[115]
Sirawaraporn, W.; Sathitkul, T.; Sirawaraporn, R.; Yuthavong, Y.; Santi, D.V. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA, 1997, 94(4), 1124-1129.
[http://dx.doi.org/10.1073/pnas.94.4.1124] [PMID: 9037017]
[116]
Rastelli, G.; Sirawaraporn, W.; Sompornpisut, P.; Vilaivan, T.; Kamchonwongpaisan, S.; Quarrell, R.; Lowe, G.; Thebtaranonth, Y.; Yuthavong, Y. Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance. Bioorg. Med. Chem., 2000, 8(5), 1117-1128.
[http://dx.doi.org/10.1016/S0968-0896(00)00022-5] [PMID: 10882022]
[117]
Yuthavong, Y.; Tarnchompoo, B.; Vilaivan, T.; Chitnumsub, P.; Kamchonwongpaisan, S.; Charman, S.A.; McLennan, D.N.; White, K.L.; Vivas, L.; Bongard, E.; Thongphanchang, C.; Taweechai, S.; Vanichtanankul, J.; Rattanajak, R.; Arwon, U.; Fantauzzi, P.; Yuvaniyama, J.; Charman, W.N.; Matthews, D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl. Acad. Sci. USA, 2012, 109(42), 16823-16828.
[http://dx.doi.org/10.1073/pnas.1204556109] [PMID: 23035243]
[118]
Drinkwater, N.; McGowan, S. From crystal to compound: structure-based antimalarial drug discovery. Biochem. J., 2014, 461(3), 349-369.
[http://dx.doi.org/10.1042/BJ20140240] [PMID: 25008945]
[119]
Kamchonwongpaisan, S.; Quarrell, R.; Charoensetakul, N.; Ponsinet, R.; Vilaivan, T.; Vanichtanankul, J.; Tarnchompoo, B.; Sirawaraporn, W.; Lowe, G.; Yuthavong, Y. Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. J. Med. Chem., 2004, 47(3), 673-680.
[http://dx.doi.org/10.1021/jm030165t] [PMID: 14736247]
[120]
Yuvaniyama, J.; Chitnumsub, P.; Kamchonwongpaisan, S.; Vanichtanankul, J.; Sirawaraporn, W.; Taylor, P.; Walkinshaw, M.D.; Yuthavong, Y. Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol., 2003, 10(5), 357-365.
[http://dx.doi.org/10.1038/nsb921] [PMID: 12704428]
[121]
Abbat, S.; Jain, V.; Bharatam, P.V. Origins of the specificity of inhibitor P218 toward wild-type and mutant PfDHFR: a molecular dynamics analysis. J. Biomol. Struct. Dyn., 2015, 33(9), 1913-1928.
[http://dx.doi.org/10.1080/07391102.2014.979231] [PMID: 25333695]
[122]
Copeland, R.A.; Pompliano, D.L.; Meek, T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov., 2006, 5(9), 730-739.
[http://dx.doi.org/10.1038/nrd2082] [PMID: 16888652]
[123]
Giridhar, R.T.R.S. •; Prajapati, D.G.S., S. •; Gupta, S.Y., M. R. Synthesis of novel 4,6-diaryl-2-aminopyrimidines as potential antiplasmodial agents. Med. Chem. Res., 2013, 22, 3309-3315.
[http://dx.doi.org/10.1007/s00044-012-0328-z]
[124]
Adane, L.; Bhagat, S.; Arfeen, M.; Bhatia, S.; Sirawaraporn, R.; Sirawaraporn, W.; Chakraborti, A.K.; Bharatam, P.V. Design and synthesis of guanylthiourea derivatives as potential inhibitors of Plasmodium falciparum dihydrofolate reductase enzyme. Bioorg. Med. Chem. Lett., 2014, 24(2), 613-617.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.009] [PMID: 24361001]
[125]
Anderson, T.J.; Patel, J.; Ferdig, M.T. Gene copy number and malaria biology. Trends Parasitol., 2009, 25(7), 336-343.
[http://dx.doi.org/10.1016/j.pt.2009.04.005] [PMID: 19559648]
[126]
Eastman, R.T.; Dharia, N.V.; Winzeler, E.A.; Fidock, D.A. Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites. Antimicrob. Agents Chemother., 2011, 55(8), 3908-3916.
[http://dx.doi.org/10.1128/AAC.01793-10] [PMID: 21576453]
[127]
Kidgell, C.; Volkman, S.K.; Daily, J.; Borevitz, J.O.; Plouffe, D.; Zhou, Y.; Johnson, J.R.; Le Roch, K.; Sarr, O.; Ndir, O.; Mboup, S.; Batalov, S.; Wirth, D.F.; Winzeler, E.A. A systematic map of genetic variation in Plasmodium falciparum. PLoS Pathog., 2006, 2(6)e57
[http://dx.doi.org/10.1371/journal.ppat.0020057] [PMID: 16789840]
[128]
Nair, S.; Miller, B.; Barends, M.; Jaidee, A.; Patel, J.; Mayxay, M.; Newton, P.; Nosten, F.; Ferdig, M.T.; Anderson, T.J. Adaptive copy number evolution in malaria parasites. PLoS Genet., 2008, 4(10)e1000243
[http://dx.doi.org/10.1371/journal.pgen.1000243] [PMID: 18974876]
[129]
Ribacke, U.; Mok, B.W.; Wirta, V.; Normark, J.; Lundeberg, J.; Kironde, F.; Egwang, T.G.; Nilsson, P.; Wahlgren, M. Genome wide gene amplifications and deletions in Plasmodium falciparum. Mol. Biochem. Parasitol., 2007, 155(1), 33-44.
[http://dx.doi.org/10.1016/j.molbiopara.2007.05.005] [PMID: 17599553]
[130]
Heinberg, A.; Siu, E.; Stern, C.; Lawrence, E.A.; Ferdig, M.T.; Deitsch, K.W.; Kirkman, L.A. Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. Mol. Microbiol., 2013, 88(4), 702-712.
[http://dx.doi.org/10.1111/mmi.12162] [PMID: 23347134]
[131]
Huang, H.; Lu, W.; Li, X.; Cong, X.; Ma, H.; Liu, X.; Zhang, Y.; Che, P.; Ma, R.; Li, H.; Shen, X.; Jiang, H.; Huang, J.; Zhu, J. Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent. Bioorg. Med. Chem. Lett., 2012, 22(2), 958-962.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.011] [PMID: 22192590]
[132]
Chen, W.; Huang, Z.; Wang, W.; Mao, F.; Guan, L.; Tang, Y.; Jiang, H.; Li, J.; Huang, J.; Jiang, L.; Zhu, J. Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely. Bioorg. Med. Chem., 2017, 25(24), 6467-6478.
[http://dx.doi.org/10.1016/j.bmc.2017.10.017] [PMID: 29111368]
[133]
Neville, A.J.; Zach, S.J.; Wang, X.; Larson, J.J.; Judge, A.K.; Davis, L.A.; Vennerstrom, J.L.; Davis, P.H. Clinically available medicines demonstrating anti-toxoplasma activity. Antimicrob. Agents Chemother., 2015, 59(12), 7161-7169.
[http://dx.doi.org/10.1128/AAC.02009-15] [PMID: 26392504]
[134]
Kongsaengdao, S.; Samintarapanya, K.; Oranratnachai, K.; Prapakarn, W.; Apichartpiyakul, C. Randomized controlled trial of pyrimethamine plus sulfadiazine versus trimethoprim plus sulfamethoxazole for treatment of toxoplasmic encephalitis in AIDS patients. J. Int. Assoc. Physicians AIDS Care (Chic.), 2008, 7(1), 11-16.
[http://dx.doi.org/10.1177/1545109707301244] [PMID: 17517949]
[135]
Pelphrey, P.M.; Popov, V.M.; Joska, T.M.; Beierlein, J.M.; Bolstad, E.S.; Fillingham, Y.A.; Wright, D.L.; Anderson, A.C. Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis. J. Med. Chem., 2007, 50(5), 940-950.
[http://dx.doi.org/10.1021/jm061027h] [PMID: 17269758]
[136]
Gangjee, A.; Qiu, Y.; Li, W.; Kisliuk, R.L. Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates. J. Med. Chem., 2008, 51(18), 5789-5797.
[http://dx.doi.org/10.1021/jm8006933] [PMID: 18800768]
[137]
Zaware, N.; Sharma, H.; Yang, J.; Devambatla, R.K.; Queener, S.F.; Anderson, K.S.; Gangjee, A. Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections. ACS Med. Chem. Lett., 2013, 4(12), 1148-1151.
[http://dx.doi.org/10.1021/ml400208v] [PMID: 24470841]
[138]
Pacheco Homem, D.; Flores, R., Jr; Tosqui, P.; de Castro Rozada, T.; Abicht Basso, E.; Gasparotto, A., Jr; Augusto Vicente Seixas, F. Homology modeling of dihydrofolate reductase from T. gondii bonded to antagonists: molecular docking and molecular dynamics simulations. Mol. Biosyst., 2013, 9(6), 1308-1315.
[http://dx.doi.org/10.1039/c3mb25530a] [PMID: 23450239]
[139]
Landau, M.J.; Sharma, H.; Anderson, K.S. Selective peptide inhibitors of bifunctional thymidylate synthasedihydrofolate reductase from Toxoplasma gondii provide insights into domain-domain communication and allosteric regulation. Protein science a publication of the Protein Society, 2013, 22, 1161-73.
[140]
Sharma, H.; Landau, M.J.; Vargo, M.A.; Spasov, K.A.; Anderson, K.S. First three-dimensional structure of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase: insights for catalysis, interdomain interactions, and substrate channeling. Biochemistry, 2013, 52(41), 7305-7317.
[http://dx.doi.org/10.1021/bi400576t] [PMID: 24053355]
[141]
Sharma, H.; Landau, M.J.; Sullivan, T.J.; Kumar, V.P.; Dahlgren, M.K.; Jorgensen, W.L.; Anderson, K.S. Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase. Bioorg. Med. Chem. Lett., 2014, 24(4), 1232-1235.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.039] [PMID: 24440298]
[142]
Thiel, M.; Harder, S.; Wiese, M.; Kroemer, M.; Bruchhaus, I. Involvement of a Leishmania thymidine kinase in flagellum formation, promastigote shape and growth as well as virulence. Mol. Biochem. Parasitol., 2008, 158(2), 152-162.
[http://dx.doi.org/10.1016/j.molbiopara.2007.12.005] [PMID: 18222009]
[143]
Chello, P.L.; Jaffe, J.J. Comparative properties of trypanosomal and mammalian thymidine kinases. Comp. Biochem. Physiol. B, 1972, 43(3), 543-562.
[http://dx.doi.org/10.1016/0305-0491(72)90138-1] [PMID: 4539354]
[144]
McNicholas, S.; Potterton, E.; Wilson, K.S.; Noble, M.E. Presenting your structures: the CCP4mg molecular-graphics software. Acta Crystallogr. D Biol. Crystallogr., 2011, 67(Pt 4), 386-394.
[http://dx.doi.org/10.1107/S0907444911007281] [PMID: 21460457]
[145]
Mol, C.D.; Harris, J.M.; McIntosh, E.M.; Tainer, J.A. Human dUTP pyrophosphatase: uracil recognition by a beta hairpin and active sites formed by three separate subunits. Structure, 1996, 4(9), 1077-1092.
[http://dx.doi.org/10.1016/S0969-2126(96)00114-1] [PMID: 8805593]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 26
ISSUE: 22
Year: 2019
Page: [4262 - 4279]
Pages: 18
DOI: 10.2174/0929867325666180926154329
Price: $58

Article Metrics

PDF: 19