Compounds were assayed for antimicrosporidial activity in an in vitro culture system and included a) approximately 20 benzimidazoles, b) approximately 25 tubulin-binding deazapteridines and deazapurines, c) 14 protease inhibitors, d) 10 angiogenesis inhibitors, e) 9 protease inhibitors with antiangiogenic activity, and f) 13 dicationic compounds. The most effective compounds tested in vitro continue to be the tubulin-binding benzimidazole, albendazole, along with two protease inhibitors with anti-angiogenic activity, fumagillin, and TNP-470. Additional compounds that have shown promise include six deazapteridines/deazapurines which are serving as root structures for synthesizing combinatorial libraries (via J. Maddry and C. Kwong). To define and characterize the targets of the lead compounds, stages of microsporidia are being separated to eventually generate cDNA libraries. Mature spores, sporoblasts, and empty spore husks have been separated using Percoll sedimentation. Meront (early proliferative stages) have not yet been enriched, however, and studies are continuing toward that goal. Two putative drug targets that are being examined genetically and biochemically include a metalloprotease inhibitor and a serine protease inhibitor. FUNDING NIH; UO1AI40324 (J. Maddry, P.I.); 09/01/96-08/31/99; $ 136,852 (year 3 directs; subcontract = approx 30% of total directs went to RPRC) NIH; UO1AI04023 (J.A. Shadduck, P.I.); 05/01/96-04/31/00;$277,178 (year 3 total direct; subcontract = approx. 50% of total directs went to RPRC) NIH; NO1-AI-75327 (E.S. Didier, P.I.); 08/15/97-08/14/02; $360,781 (year 2 directs; 100% to RPRC) PUBLICATIONS Abstracts Didier, E.S., J.A. Maddry, C.D. Kwong, J.M. Orenstein, K.F. Snowden, and J.A. Shadduck. 1998. Effects of tubulin-binding compounds and antiangiogenic agents on microsporidium growth in vitro. National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections (abstract). Maddry, J.A., X. Chen, E.S. Didier, and C.D. Kwong. 1998. Combinatorial chemistry in drug discovery for microsporidal infections. National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections (abstract). Didier, E.S., and D.C. Bertucci. 1998. Effects of antiangiogenic agents on the growth of microsporidia in vitro. Amer. J. Trop. Med. Hyg. 59:332 (abstract 646). Didier, E.S., L.C. Green, D.C. Bertucci, J.M. Orenstein, K.F. Snowden, and J.A. Shadduck. 1999. Effects of angiogenesis and protease inhibitors on microsporidia growth in vitro. Sixth Conference on Retroviruses and Opportunistic Infections (abstract 699). Didier, E.S., D.C. Bertucci, J. Leblanc. 1999. Inhibition of microsporidia growth in vitro. Amer. Soc. Microbiol. (Abstract A52). Peer-reviewed publications Didier, E.S., J.A. Maddry, C.D. Kwong, L.C. Green, and J.A. Shadduck. 1998. Screening of compounds for antimicrosporidial activity in vitro. Folia Parasitol. 45:129-139. Green, L.C., P.J. Didier, and E.S. Didier. 1999. Fractionation of sporogonial stages of the microsporidian Encephalitzoon cuniculi by Percoll gradients. J. Euk. Microbiol. (in press) Reviews and book chapters Didier, E.S. 1998. State-of-the-Art Clinical Article Microsporidiosis. Clin. Infect. Dis. 27:1-7. Soave, R. and E.S. Didier. 1999. Cryptosporidium and Microsporidium. In Textbook of AIDS Medicine (2nd ed.). T.C. Merigan, J.G. Bartlett, and D. Bolognesi (eds.). Williams and Wilkins, Baltimore, MD. pp. 327-356.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000164-41
Application #
6591737
Study Section
Project Start
2002-05-01
Project End
2003-04-30
Budget Start
Budget End
Support Year
41
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Tulane University
Department
Type
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Mahalingam, Ravi; Kaufer, Benedikt B; Ouwendijk, Werner J D et al. (2018) Attenuation of Simian Varicella Virus Infection by Enhanced Green Fluorescent Protein in Rhesus Macaques. J Virol 92:
Kumar, Vinay; Mansfield, Joshua; Fan, Rong et al. (2018) miR-130a and miR-212 Disrupt the Intestinal Epithelial Barrier through Modulation of PPAR? and Occludin Expression in Chronic Simian Immunodeficiency Virus-Infected Rhesus Macaques. J Immunol 200:2677-2689
Parthasarathy, Geetha; Philipp, Mario T (2018) Intracellular TLR7 is activated in human oligodendrocytes in response to Borrelia burgdorferi exposure. Neurosci Lett 671:38-42
McNamara, Ryan P; Costantini, Lindsey M; Myers, T Alix et al. (2018) Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses. MBio 9:
Calenda, Giulia; Villegas, Guillermo; Barnable, Patrick et al. (2017) MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa. J Acquir Immune Defic Syndr 74:e67-e74
Datta, Dibyadyuti; Bansal, Geetha P; Grasperge, Brooke et al. (2017) Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques. Vaccine 35:7049-7056
Yi, Fei; Guo, Jia; Dabbagh, Deemah et al. (2017) Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1. J Virol 91:
Jorgensen, Matthew J; Lambert, Kelsey R; Breaux, Sarah D et al. (2017) Pair housing of Vervets/African Green Monkeys for biomedical research. Am J Primatol 79:1-10
Ramesh, Geeta; Martinez, Alejandra N; Martin, Dale S et al. (2017) Effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in glial and neuronal cells of the central nervous system. J Neuroinflammation 14:28
Parthasarathy, Geetha; Philipp, Mario T (2017) Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi. J Neuroinflammation 14:110

Showing the most recent 10 out of 352 publications