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.
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