title: Synthetic chondramide A analogues stabilize filamentous actin and block invasion by Toxoplasma gondii.
abstract: Apicomplexan parasites such as Toxoplasma gondii rely on actin-based motility to cross biological barriers and invade host cells. Key structural and biochemical differences in host and parasite actins make this an attractive target for small-molecule inhibitors. Here we took advantage of recent advances in the synthesis of cyclic depsipeptide compounds that stabilize filamentous actin to test the ability of chondramides to disrupt growth of T. gondii in vitro. Structural modeling of chondramide A (2) binding to an actin filament model revealed variations in the binding site between host and parasite actins. A series of 10 previously synthesized analogues (2b-k) with substitutions in the β-tyrosine moiety blocked parasite growth on host cell monolayers with EC₅₀ values that ranged from 0.3 to 1.3 μM. In vitro polymerization assays using highly purified recombinant actin from T. gondii verified that synthetic and natural product chondramides target the actin cytoskeleton. Consistent with this, chondramide treatment blocked parasite invasion into host cells and was more rapidly effective than pyrimethamine, a standard therapeutic agent. Although the current compounds lack specificity for parasite vs host actin, these studies provide a platform for the future design and synthesis of synthetic cyclic peptide inhibitors that selectively disrupt actin dynamics in parasites.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Ma
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Diraviyam
authors.forename: Martin E
authors.initials: ME
authors.lastname: Maier
authors.forename: David
authors.initials: D
authors.lastname: Sept
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D014122:Toxoplasma / Q000187:drug effects* / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D008840:Microfilament Proteins; D015800:Protozoan Proteins; C097819:chondramide A
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