Abstract

This application has been constructed to provide a focused effort designed to produce new drugs to treat patients infected with Pneumocystis carinii, Toxoplasma gondii, or cytomegalovirus infections. The groups include synthetic organic chemists whose goal will be to synthesize new candidate compounds with the aim of identifying agents of greater potency as well as selectivity, biological scientists who will seek to isolate and characterize key enzymes of P. carinii and T. gondii and who will also evaluate the new synthetic compounds for their efficacy against T. gondii both in vitro and in vivo, and virologists who will seek to identify new agents effective against cytomegalovirus in a screening program on selected compounds provided by Du Pont, our industrial partner. Compounds from the synthesis program will also be evaluated against P. carinii in programs at Indiana University sponsored by NIAID.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI030279-03
Application #
3547646
Study Section
Special Emphasis Panel (SRC (76))
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205

  Publications

Reynolds, Robert C; Campbell, Shiela R; Fairchild, Ralph G et al. (2007) Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation. J Med Chem 50:3283-9
Klon, Anthony E; Heroux, Annie; Ross, Larry J et al. (2002) Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol 320:677-93
White, E L; Ross, L J; Davis, R L et al. (2000) The two toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase isozymes form heterotetramers. J Biol Chem 275:19218-23
Suling, W J; Seitz, L E; Pathak, V et al. (2000) Antimycobacterial activities of 2,4-diamino-5-deazapteridine derivatives and effects on mycobacterial dihydrofolate reductase. Antimicrob Agents Chemother 44:2784-93
Heroux, A; White, E L; Ross, L J et al. (1999) Crystal structures of the Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase-GMP and -IMP complexes: comparison of purine binding interactions with the XMP complex. Biochemistry 38:14485-94
Shoen, C M; Choromanska, O; Reynolds, R C et al. (1998) In vitro activities of several diaminomethylpyridopyrimidines against Mycobacterium avium complex. Antimicrob Agents Chemother 42:3315-6
Piper, J R; Johnson, C A; Krauth, C A et al. (1996) Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. J Med Chem 39:1271-80
Vasanthakumar, G; van Ginkel, S; Parish, G (1994) Isolation and sequencing of a cDNA encoding the hypoxanthine-guanine phosphoribosyltransferase from Toxoplasma gondii. Gene 147:153-4
Pfefferkorn, E R; Borotz, S E (1994) Toxoplasma gondii: characterization of a mutant resistant to 6-thioxanthine. Exp Parasitol 79:374-82
Piper, J R; Johnson, C A; Hosmer, C A et al. (1993) Lipophilic antifolates as candidates against opportunistic infections. Adv Exp Med Biol 338:429-33