Parasites of the phylum Apicomplexa rely on actin-based motility for invasion of host cells. Included in this group are the opportunistic pathogens Toxoplasma gondii and Cryptosporidium spp. Infections with these opportunistic pathogens remain important complications of AIDS, especially in populations where effective anti-HIV therapies are not widely available. More effective drugs to combat these opportunistic infections are sorely needed and fundamental studies of parasite biology have the potential to identify new targets. Our preliminary studies have revealed important structural, molecular, and kinetic differences in the parasite cytoskeleton. Gliding motility and cell invasion by these parasites depend on the rapid assembly and turnover of actin filaments. Hence, agents that disrupt the actin cytoskeleton are highly toxic to these parasites. A combination of cell biological, biochemical, genetic, and molecular modeling approaches will be used to explore the cytoskeleton in parasites. Fundamental knowledge from these studies will be used to design and synthesize specific inhibitors of the cytoskeleton in parasites. Inhibitors will be screened in vitro and in vivo for activity against the parasite Toxoplasma. The proposed studies have the potential to provide new anti-parasitic agents for control of toxoplasmosis, cryptosporidiosis, and possibly other opportunistic infections in immunocompromised patients with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073155-05
Application #
8107541
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rogers, Martin J
Project Start
2007-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$342,820
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Danner, Paulami; Morkunas, Marius; Maier, Martin E (2013) Synthesis of D-abrines by palladium-catalyzed reaction of ortho-iodoanilines with N-Boc-N-methylalanyl-substituted acetaldehyde and acetylene. Org Lett 15:2474-7
Skillman, Kristen M; Ma, Christopher I; Fremont, Daved H et al. (2013) The unusual dynamics of parasite actin result from isodesmic polymerization. Nat Commun 4:2285
Ma, Christopher I; Diraviyam, Karthikeyan; Maier, Martin E et al. (2013) Synthetic chondramide A analogues stabilize filamentous actin and block invasion by Toxoplasma gondii. J Nat Prod 76:1565-72
Skillman, Kristen M; Daher, Wassim; Ma, Christopher I et al. (2012) Toxoplasma gondii profilin acts primarily to sequester G-actin while formins efficiently nucleate actin filament formation in vitro. Biochemistry 51:2486-95
Skillman, Kristen M; Diraviyam, Karthikeyan; Khan, Asis et al. (2011) Evolutionarily divergent, unstable filamentous actin is essential for gliding motility in apicomplexan parasites. PLoS Pathog 7:e1002280
Yadav, Rahul; Pathak, Prem Prakash; Shukla, Vaibhav Kumar et al. (2011) Solution structure and dynamics of ADF from Toxoplasma gondii. J Struct Biol 176:97-111
Zhdanko, Alexander; Schmauder, Anke; Ma, Christopher I et al. (2011) Synthesis of chondramide A analogues with modified ?-tyrosine and their biological evaluation. Chemistry 17:13349-57
Mehta, Simren; Sibley, L David (2011) Actin depolymerizing factor controls actin turnover and gliding motility in Toxoplasma gondii. Mol Biol Cell 22:1290-9
Gordon, Jennifer L; Buguliskis, Jeffrey S; Buske, Paul J et al. (2010) Actin-like protein 1 (ALP1) is a component of dynamic, high molecular weight complexes in Toxoplasma gondii. Cytoskeleton (Hoboken) 67:23-31
Mehta, Simren; Sibley, L David (2010) Toxoplasma gondii actin depolymerizing factor acts primarily to sequester G-actin. J Biol Chem 285:6835-47

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