Potential Opportunity in the Development of New Therapeutic Agents Based on Endogenous and Exogenous Inhibitors of the Proprotein Convertases

Bontemps, Yannick; Scamuffa, Nathalie; Calvo, Fabien; Khatib, Abdel‐Majid

doi:10.1002/chin.200747226

Cited by 5 publications

(6 citation statements)

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“…In our studies, we used multiple approaches, including T cell lines, PBMCs, and T cells from healthy and patients with colon cancer as well as a syngeneic mouse tumor model, to study the role of the PCs in PD-1 expression and the signaling pathways involved in PD-1 repression by PCs inhibition. We have shown that furin and PC7 are the main PC family members expressed in T cells, and therefore we have used the general PC inhibitors a1-PDX and CMK known to efficiently repress the activity of both PCs (29,30). We have shown that PC inhibitors impede PD-1 expression in activated hPBMCs and T cells, and promote proliferation and survival.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer

et al. 2019

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Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor a1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-kB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer

et al. 2019

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“…In the mouse model, P‐domain folding of proprotein convertase (PCSK5) was recently shown to be critical for its activity, and abnormal folding of the P‐domain induced serious cellular defects in development, showing the importance of the P‐domain in cellular processing (Szumska et al ., 2008). Because of the importance of convertases, inhibitors of these enzymes have been studied as potential therapeutic agents for various diseases (Bontemps et al ., 2007), and many synthetic convertase inhibitors have been evaluated (Basak, 2005). However, relatively few natural convertase inhibitors have been reported.…”

Section: Discussionmentioning

confidence: 99%

Complex extracellular interactions of proteases and a protease inhibitor influence multicellular development of Streptomyces coelicolor

Kim

Hesketh

Kim

et al. 2008

Molecular Microbiology

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SummaryStreptomyces coelicolor produces an extracellular protease inhibitor protein, STI (Streptomyces trypsin inhibitor). We show that post-growth elimination of STI is needed for colonies to develop aerial mycelium efficiently. Inactivation of STI, and thus the normal progression of colony development, at least partly involves an extracellular protease specified by gene SCO5913. Two-hybrid analysis identified two possible targets of STI inhibition (the products of SCO1355 and SCO5447), both extracellular proteases containing a domain homologous with the P-domain of eukaryotic convertases, proteases that mediate the processing of many precursors with important cellular or developmental roles. At least the SCO1355 protease is needed for the normal progression of development. Two components of the proposed cascade are dependent on the tRNA for the rare UUA (leucine) codon, which is specified by the developmental gene bldA. A model is presented that links intracellular regulatory events with an extracellular protease cascade to facilitate normal development.

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“…Compared to other arginine-specific proteases, such as the trypsin-like serine proteases thrombin and factor Xa, only moderate progress has been achieved in the field of PC inhibitors. PCs are inhibited by various naturally occurring macromolecular protein-based inhibitors; additional bioengineered inhibitors have been designed by incorporation of the PC’s consensus sequence into variants of the serpin α1-antitrypsin, the leech-derived eglin C, and the third domain of turkey ovomucoid. , Most of the small molecule PC inhibitors belong to three groups, pure peptides, peptide mimetics, or nonpeptidic compounds. Peptides derived from the PC prodomains or identified from a combinatorial library inhibit furin and some related PCs in the micromolar range .…”

Section: Introductionmentioning

confidence: 99%

Potent Inhibitors of Furin and Furin-like Proprotein Convertases Containing Decarboxylated P1 Arginine Mimetics

et al. 2009

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Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporation of decarboxylated arginine mimetics in P1 position of substrate analogue peptidic inhibitors we could identify highly potent furin inhibitors. The most potent compound, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (15), inhibits furin with a K i -value of 0.81 nM and has also comparable affinity to other PCs like PC1/3, PACE4, and PC5/6, whereas PC2 and PC7 or trypsin-like serine proteases were poorly affected. In fowl plague virus (influenza A, H7N1)-infected MDCK cells inhibitor 15 reduced proteolytic hemagglutinin cleavage and was able to reduce virus propagation in a long term infection test. Molecular modelling revealed several key interactions of the 4-amidinobenzylamide residue in the S1 pocket of furin contributing to the excellent affinity of these inhibitors.

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Potential Opportunity in the Development of New Therapeutic Agents Based on Endogenous and Exogenous Inhibitors of the Proprotein Convertases

Abstract: Proprotein Convertases -[78 refs.]. -(BONTEMPS, Y.; SCAMUFFA, N.; CALVO, F.; KHATIB*, A.-M.; Med. Res. Rev. 27 (2007) 5, 631-648; INSERM, Inst. Genet. Mol., Equipe AVENIR, F-75010 Paris, Fr.; Eng.) -Lindner 47-226

Cited by 5 publications

References 1 publication

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer

Complex extracellular interactions of proteases and a protease inhibitor influence multicellular development of Streptomyces coelicolor

Potent Inhibitors of Furin and Furin-like Proprotein Convertases Containing Decarboxylated P1 Arginine Mimetics

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