Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi

Joyeau, Roger; Maoulida, Chanfi; Guillet, Cindy; Frappier, François; Teixeira, Antônio R. L.; Schrével, Joseph; Santana, Jaime M.; Grellier, Philippe

doi:10.1016/s0223-5234(00)00118-5

Cited by 29 publications

(30 citation statements)

References 36 publications

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“…All of these compounds are reversible competitive inhibitors of POP Tc80 (Ref. 18; data not shown). Selected T. cruzi proteases were oligopeptidase B, a serine protease involved in the host cell invasion process (12)(13)(14); cruzipain, a cathepsin-L like protease whose inhibition impairs parasite development (15,35); and Tc30 cysteine-proteinase, a cathepsin-B like protease (23,36), since there is evidence that resistance to cruzipain inhibitors is associated with a high level of cathepsin-B expression by the parasite (37).…”

Section: Tc80 Proteinase Is a Member Of The Prolyl Oligopeptidase Fammentioning

confidence: 91%

“…Z-LGP-vinyl sulfone, -ketobenzothiazole, and -nitrile were synthesized as described (18). Inhibitor 1 was synthesized as previously reported (20).…”

Section: Methodsmentioning

confidence: 99%

“…Compartment Surrounding the Flagellar Pocket of Trypomastigotes-Based on its biochemical properties (postproline activity, sensitivity to the inhibitors diisopropyl fluorophosphate and p-chloromercuribenzoate, and insensitivity to phenylmethylsulfonyl fluoride), the Tc80 proteinase could be classified into the POP family (18,20). However, a previously obtained internal amino acid sequence showed no similarity to POPs and to other T. cruzi proteases (16).…”

Section: Tc80 Proteinase Is a Member Of The Prolyl Oligopeptidase Fammentioning

confidence: 99%

“…By its property of cleaving peptide bonds at the carboxyl side of proline residues, Tc80 proteinase could be classified as prolyl oligopeptidase (POP), a representative of a new serine peptidase family (EC 3.4.21.26) (17). As POPs, Tc80 proteinase has an unusual inhibitor profile characterized by its inactivation by diisopropyl fluorophosphate but not by the serine protease inhibitor phenylmethylsulfonyl fluoride and its susceptibility to p-chloromercuribenzoate, a cysteine protease inhibitor, indicating the presence of a cysteine residue at or near the active site (18). Tc80 proteinase secretion by the trypomastigotes suggests that this enzyme could be involved in the host cell infection by facilitating the parasite migration through ECM or the host cell invasion per se (e.g.…”

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confidence: 99%

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Trypanosoma cruzi Prolyl Oligopeptidase Tc80 Is Involved in Nonphagocytic Mammalian Cell Invasion by Trypomastigotes

Grellier¹,

Vendeville²,

Joyeau³

et al. 2001

Journal of Biological Chemistry

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116

106

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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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Section: Tc80 Proteinase Is a Member Of The Prolyl Oligopeptidase Fammentioning

confidence: 91%

“…Z-LGP-vinyl sulfone, -ketobenzothiazole, and -nitrile were synthesized as described (18). Inhibitor 1 was synthesized as previously reported (20).…”

Section: Methodsmentioning

confidence: 99%

Section: Tc80 Proteinase Is a Member Of The Prolyl Oligopeptidase Fammentioning

confidence: 99%

mentioning

confidence: 99%

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Trypanosoma cruzi Prolyl Oligopeptidase Tc80 Is Involved in Nonphagocytic Mammalian Cell Invasion by Trypomastigotes

Grellier¹,

Vendeville²,

Joyeau³

et al. 2001

Journal of Biological Chemistry

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116

106

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“…NCL is an ATP-binding protein (32) that affects protein-protein and protein-nucleic acid interactions relevant to ribosomal and mRNA transcription, transport, and stability (33). ATP-agarose beads were used to evaluate the relative affinity of NCL versus EBNA1 for ATP.…”

Section: Ncl Is Essential For Ebna1 Binding To Orip and Episome Maintmentioning

confidence: 99%

Nucleolin is important for Epstein–Barr virus nuclear antigen 1-mediated episome binding, maintenance, and transcription

Chen

Liu

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is essential for EBV episome maintenance, replication, and transcription. These effects are mediated by EBNA1 binding to cognate oriP DNA, which comprise 20 imperfect copies of a 30-bp dyad symmetry enhancer and an origin for DNA replication. To identify cell proteins essential for these EBNA1 functions, EBNA1 associated cell proteins were immune precipitated and analyzed by liquid chromatography-tandem mass spectrometry. Nucleolin (NCL) was identified to be EBNA1 associated. EBNA1's N-terminal 100 aa and NCL's RNA-binding domains were critical for EBNA1/NCL interaction. Lentivirus shRNA-mediated NCL depletion substantially reduced EBNA1 recruitment to oriP DNA, EBNA1-dependent transcription of an EBV oriP luciferase reporter, and EBV genome maintenance in lymphoblastoid cell lines. NCL RNA-binding domain K 429 was critical for ATP and EBNA1 binding. NCL overexpression increased EBNA1 binding to oriP and transcription, whereas NCL K 429 A was deficient. Moreover, NCL silencing impaired lymphoblastoid cell line growth. These experiments reveal a surprisingly critical role for NCL K429 in EBNA1 episome maintenance and transcription, which may be a target for therapeutic intervention.lymphoma | chromatin | oncogenic herpesvirus | nasopharyngeal carcinoma

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Simple Proline‐Derived Phosphine‐Thiazole Iridium Complexes for Asymmetric Hydrogenation of Trisubstituted Olefins

et al. 2013

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Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi

Cited by 29 publications

References 36 publications

Trypanosoma cruzi Prolyl Oligopeptidase Tc80 Is Involved in Nonphagocytic Mammalian Cell Invasion by Trypomastigotes

Trypanosoma cruzi Prolyl Oligopeptidase Tc80 Is Involved in Nonphagocytic Mammalian Cell Invasion by Trypomastigotes

Nucleolin is important for Epstein–Barr virus nuclear antigen 1-mediated episome binding, maintenance, and transcription

Simple Proline‐Derived Phosphine‐Thiazole Iridium Complexes for Asymmetric Hydrogenation of Trisubstituted Olefins

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