Trypanosoma cruzi is an intracellular protozoan parasite able to invade a wide variety of mammalian cells. To have access to the target organs/cells, the parasite must cross the basal laminae and the extracellular matrix (ECM). We previously characterized an 80-kDa proteinase (Tc80) secreted by the infective trypomastigotes that hydrolyzes native collagens and might be involved in infection by degrading ECM components. Here, we present evidence indicating a role for Tc80 in the invasion of nonphagocytic cells. Tc80 was classified as a member of the prolyl oligopeptidase (POP) family of serine proteases and was also found to hydrolyze fibronectin. Selective inhibitors for POP Tc80 were synthesized that blocked parasite entry into cells. Blockage occurred when trypomastigotes were preincubated with irreversible inhibitors but not after host cell preincubation, and the blockage correlated with inhibition of POP Tc80 activity in treated parasites. These data and the enzyme location inside a vesicular compartment close to the flagellar pocket, a specialized domain in endocytosis/exocytosis, strongly suggest a role for POP Tc80 in the maturation of parasite protein(s) and/or, after secretion, in a local action on parasite or host cell/ECM components required for invasion.

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Piptadenia pervillei Vatke (Fabaceae) was selected from a screening programme devoted to the search of naturally-occuring antimalarial compounds from plants of Madagascar. Bioassay-guided fractionation of the ethyl acetate extract of the leaves led to the isolation of four phenolic compounds, (+)-catechin ( 1), (+)-catechin 5-gallate ( 2), (+)-catechin 3-gallate ( 3) and ethyl gallate ( 4). Structures were determined by NMR and mass spectroscopy. Compounds 2 and 3 displayed the highest in vitro activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum with IC (50) values of 1.2 microM and 1.0 microM, respectively, and no significant cytotoxicity against the human embryonic lung cells MRC-5 was measured (IC (50) values > 75 microM). Five analogues ( 5 - 9) of (+)-catechin 5-gallate ( 2) were synthesized and evaluated for their antiplasmodial activity.

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A I'unetionalixcd N.ar~'l .zetidinon¢ ha~t been drown to inactivate human leukt~eyt¢ ela=ta~ [HLE) and porcine panereatle elaMa~¢ (PPE) by an enzyme.mediated pro~¢=~. The inactivation is characterized by the t'ollewtn~ kinetic ¢on~ta nt~ at pH tk0 and ~7'C: k,p,.+~ -0,0~.~ s = z. g~ ~ 1,2 ~ I 0 =* M for HLE, 0,08 =t *~ and 2.'1 x 10 ''~ M for PPE, te,tpeetively. Two parent moleeule~¢ dc~voitt or the latent leavintl sroup tidied to inactivate HLE and PPE and bchawd as ~ubstrates of these enzymes, A ~uicide mechanism i~ postulated inv~lvinll the formation or an acyl-enxyme and the simuha. neous unmaskin$ of a latent quinonimmonium m~thid¢ ion which irrever~ib!y reacts with an active ~it© nudeophil¢. Moreover. the inhibitor t~ still ¢fl'~tive at inhibitinlt elasla~ preab~orbed ol~to ela~tin, /i.Laetam: Leukocyte ¢lastase; Suicide ~ub~trale

N-(3-Carboxy-6-methylphenyl)-3-fluoroazetidin-2-one and a series of related N-aryl-3-halo- and -3,3-dihaloazetidinones 3, in which the halo substituent is a fluorine or a bromine atom, were prepared by using the Wasserman procedure of cyclization of beta-bromopropionamides as a key step. Their affinities for the TEM-1 beta-lactamase were determined and compared with those of a series of tricyclic azetidinones, the benzocarbacephems 2, and known beta-lactamase inhibitors. The beta-lactams 2 and 3 behave as competitive inhibitors and not as substrates of the enzyme; neither halogen substitution (series 3) nor ring strain (series 2) induces enzymatic hydrolysis.

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