Biopolym. Cell. 1994; 10(6):65-71.
Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases
1Craig S.
  1. Department Biochemistry, University of Puerto Rico, School of Medicine
    San Juan, 00936-5067, Puerto Rico


The review analyses the results showing that technological advances in studying the specific target molecules in a cell allow to develop new effective drugs for the treatment of a number of human maladies. The new approach to the drug design is based In the data of enzyme structure.


[1] Yuan L, Craig SP 3rd, McKerrow JH, Wang CC. Steady-state kinetics of the schistosomal hypoxanthine-guanine phosphoribosyltransferase. Biochemistry. 1992;31(3):806-10.
[2] Queen SA, Jagt DL, Reyes P. In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism. Antimicrob Agents Chemother. 1990;34(7):1393-8.
[3] Amann E, Brosius J, Ptashne M. Vectors bearing a hybrid trp-lac promoter useful for regulated expression of cloned genes in Escherichia coli. Gene. 1983;25(2-3):167-78.
[4] Tabor S, Richardson CC. A bacteriophage T7 RNA polymerase/promoter system for controlled exclusive expression of specific genes. Proc Natl Acad Sci U S A. 1985;82(4):1074-8.
[5] Studier FW, Moffatt BA. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes. J Mol Biol. 1986;189(1):113-30.
[6] Craig SP 3rd, Yuan L, Kuntz DA, McKerrow JH, Wang CC. High level expression in Escherichia coli of soluble, enzymatically active schistosomal hypoxanthine/guanine phosphoribosyltransferase and trypanosomal ornithine decarboxylase. Proc Natl Acad Sci U S A. 1991;88(6):2500-4.
[7] Shoichet BK, Stroud RM, Santi DV, Kuntz ID, Perry KM. Structure-based discovery of inhibitors of thymidylate synthase. Science. 1993;259(5100):1445-50.
[8] Ring CS, Sun E, McKerrow JH, Lee GK, Rosenthal PJ, Kuntz ID, Cohen FE. Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci U S A. 1993;90(8):3583-7.
[9] Appelt K, Bacquet RJ, Bartlett CA, Booth CL, Freer ST, Fuhry MA, Gehring MR, Herrmann SM, Howland EF, Janson CA, et al. Design of enzyme inhibitors using iterative protein crystallographic analysis. J Med Chem. 1991;34(7):1925-34.
[10] Ericson IW, Fesik SW. Macromolecular X-ray crystallography and NMR as tools for structure-based drug design. Chapt. 29 of section VI: Topics in drug design and discovery. Ed. M. C. Venuti. Ann. Rep. Med. Chem. New York : Acad, press, 1922. Vol. 27: 271-289.
[11] Varney MD, Marzoni GP, Palmer CL, Deal JG, Webber S, Welsh KM, Bacquet RJ, Bartlett CA, Morse CA, Booth CL, et al. Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase. J Med Chem. 1992;35(4):663-76.
[12] Gilman AG, Rail TW, Nies AS, Taylor P. Gilman's the pharmacological basis of therapeutics. New York : Pergamon press, 1990.
[13] Rosowsky A, Mota CE, Wright JE, Freisheim JH, Heusner JJ, McCormack JJ, Queener SF. 2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J Med Chem. 1993;36(21):3103-12.
[14] Margosiak SA, Appleman JR, Santi DV, Blakley RL. Dihydrofolate reductase from the pathogenic fungus Pneumocystis carinii: catalytic properties and interaction with antifolates. Arch Biochem Biophys. 1993;305(2):499-508.
[15] Chio LC, Queener SF. Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase. Antimicrob Agents Chemother. 1993;37(9):1914-23.
[16] Peterson DS, Milhous WK, Wellems TE. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. Proc Natl Acad Sci U S A. 1990;87(8):3018-22.
[17] Schecter PO, Barlow JLR, Sjoerdsma A. Clinical aspects of inhibition of ornithine decarboxylase with emphasis on therapeutic trial's of eflornithine (DEMO) in cancer and protozoan diseases. Inhibition of polyamine metabolism. Eds P. P. McCann, A. E. Pegg, A. Sjoerdsma. New York: Acad, press, 1987: 345-364.
[18] Slater AF, Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature. 1992;355(6356):167-9.
[19] Wellems TE. Malaria. How chloroquine works. Nature. 1992;355(6356):108-9.
[20] Walsh CJ, Sherman IW. Purine and pyrimidine synthesis by the avian malaria parasite, Plasmodium lophurae. J Protozool. 1968;15(4):763-70.
[21] Sherman IW. Biochemistry of Plasmodium (malarial parasites). Microbiol Rev. 1979;43(4):453-95.
[22] Marr JJ, Berens RL, Nelson DJ. Purine metabolism in Leishmania donovani and Leishmania braziliensis. Biochim Biophys Acta. 1978;544(2):360-71.
[23] Wang CC, Aldritt S. Purine salvage networks in Giardia lamblia. J Exp Med. 1983;158(5):1703-12.
[24] Berens RL, Marr JJ, LaFon SW, Nelson DJ. Purine metabolism in Trypanosoma cruzi. Mol Biochem Parasitol. 1981;3(3):187-96.
[25] Senft AW, Crabtree GW. Purine metabolism in the schistosomes: potential targets for chemotherapy. Pharmacol Ther. 1983;20(3):341-56.
[26] Wang CC, Verham R, Rice A, Tzeng S. Purine salvage by Tritrichomonas foetus. Mol Biochem Parasitol. 1983;8(4):325-37.
[27] Jolly DJ, Okayama H, Berg P, Esty AC, Filpula D, Bohlen P, Johnson GG, Shively JE, Hunkapillar T, Friedmann T. Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase. Proc Natl Acad Sci U S A. 1983;80(2):477-81.
[28] Craig SP 3rd, McKerrow JH, Newport GR, Wang CC. Analysis of cDNA encoding the hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) of Schistosoma mansoni; a putative target for chemotherapy. Nucleic Acids Res. 1988;16(14B):7087-101.
[29] King A, Melton DW. Characterisation of cDNA clones for hypoxanthine-guanine phosphoribosyltransferase from the human malarial parasite, Plasmodium falciparum: comparisons to the mammalian gene and protein. Nucleic Acids Res. 1987;15(24):10469-81.
[30] Allen TE, Ullman B. Cloning and expression of the hypoxanthine-guanine phosphoribosyltransferase gene from Trypanosoma brucei. Nucleic Acids Res. 1993;21(23):5431-8.
[31] Chin MS, Wang CC. Isolation, sequencing and expression of the gene encoding hypoxanthine-guanine-xanthine phosphoribosyltransferase of Tritrichomonas foetus. Mol Biochem Parasitol. 1994;63(2):221-9.
[32] Showalter RE, Silverman MR. Nucleotide sequence of a gene, hpt, for hypoxanthine phosphoribosyltransferase from Vibrio harveyi. Nucleic Acids Res. 1990;18(15):4621.
[33] Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science. 1967;155(3770):1682-4.
[34] Kelley WN, Greene ML, Rosenbloom FM, Henderson JF, Seegmiller JE. Hypoxanthine-guanine phosphoribosyltransferase deficiency in gout. Ann Intern Med. 1969;70(1):155-206.
[35] Eakin AE, Nieves-Alicea R, Tosado-Acevedo R, Chin MS, Wang CC, Craig SP 3rd. Comparative complement selection in bacteria enables screening for lead compounds targeted to a purine salvage enzyme of parasites. Antimicrob Agents Chemother. 1995;39(3):620-5.
[36] Marr JJ. Purine analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. J Lab Clin Med. 1991;118(2):111-9.
[37] The Merck index: An encyclopedia of chemicals, drugs, and biologicals. Eds S. Budavari et al. New York : Merck and Co, 1989.
[38] Scapin G, Grubmeyer C, Sacchettini JC. Crystal structure of orotate phosphoribosyltransferase. Biochemistry. 1994;33(6):1287-94.
[39] Davidson BL, TarlГ© SA, Palella TD, Kelley WN. Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts. J Clin Invest. 1989;84(1):342-6.
[40] Foote SJ, Galatis D, Cowman AF. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci U S A. 1990;87(8):3014-7.
[41] Sirawaraporn W, Prapunwattana P, Sirawaraporn R, Yuthavong Y, Santi DV. The dihydrofolate reductase domain of Plasmodium falciparum thymidylate synthase-dihydrofolate reductase. Gene synthesis, expression, and anti-folate-resistant mutants. J Biol Chem. 1993;268(29):21637-44.
[42] Erickson J, Neidhart DJ, VanDrie J, Kempf DJ, Wang XC, Norbeck DW, Plattner JJ, Rittenhouse JW, Turon M, Wideburg N, et al. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science. 1990;249(4968):527-33.
[43] Bugg CE, Carson WM, Montgomery JA. Drugs by desing: Structure-based design, an inovative approach to developing drugs, has recently spawned many promising therapeutic agents, including several now in human trials for treating AIDS, cancer and other diseases. Scientific Am. 1993; 269: 92-98.
[44] Lam PY, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, et al. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science. 1994;263(5145):380-4.