Targeting the Actin Cytoskeleton in Parasites

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. <P> 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. <P> 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. <P> 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.