key: cord-0818668-tnaimz3c
authors: Bontemps, Yannick; Scamuffa, Nathalie; Calvo, Fabien; Khatib, Abdel‐Majid
title: Potential opportunity in the development of new therapeutic agents based on endogenous and exogenous inhibitors of the proprotein convertases
date: 2006-10-03
journal: Med Res Rev
DOI: 10.1002/med.20072
sha: 5205f37f2ade8b83dade06ac8e7674efcf4913c4
doc_id: 818668
cord_uid: tnaimz3c

The proprotein convertases (PCs) are responsible for the endoproteolytic processing of various protein precursors (e.g., growth factors, receptors, adhesion molecules, and matrix metalloproteinases) implicated in several diseases such as obesity, diabetes, atherosclerosis, cancer, and Alzheimer disease. The potential clinical and pharmacological role of the PCs has fostered the development of various PC‐inhibitors. In this review we summarized the recent findings on PCs inhibitors, their mode of actions and potential use in the therapy of various diseases. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 5, 631–648, 2007

The proprotein convertases (PCs) are serine proteases that bellow to the kexin subfamily of subtilases enzymes responsible for the processing and the activation of multiple polypeptide precursors. These secretory precursors are usually cleaved at the general motif (K/R)-(X)n-(K/R)#, where X is any amino acid (except C), n ¼ 0, 2, 4, or 6, and # represents the cleavage site where the peptide is hydrolyzed. [1] [2] [3] [4] [5] [6] To date, seven basic amino acids (AA)-specific PCs, serine proteases belonging to the kexin subfamily of subtilases, were reported to be involved in these processes. [1] [2] [3] [4] [5] [6] These include Furin, PC1 (also called PC3), PC2, PC4, PACE4, PC5 (also called PC6), and PC7 (also called PC8, LPC, or SPC7). [1] [2] [3] [4] [5] [6] Recently, other two nonbasic-AA-specific convertases, SKI-1 7, 8 and NARC-1 9 were identified. These convertases belong to the Pyrolysin and Proteinase K subfamily of subtilases, respectively. While, SKI-1 was found to exhibit a cleavage specificity for the motif (R/K)-X-(hydrophobic)-(L,T)#, based on its autocatalytic site, NARC-1 seems to prefer the V-F-A-Q# motif. 10 In this review, the role of the proprotein convertases in the mediation of some diseases will be briefly summarized, the mode of action of their natural and exogenous inhibitors will be described and their potential use as new targets for the treatment of various diseases will be discussed.

Recently PCs have been linked to some neurodegenerative disorders via their direct or indirect roles in the production of amyloidogenic peptides. In Alzheimer's disease the amyloid-b (Ab) is the principal component of senile plaques. The latter is generated by proteolytic cleavage of its precursor by band g-secretases. Recently, the PCs were found to process the zymogens of both aand b-secretases, suggesting the implicating of the PCs in this disease. 11, 12 

The involvement of proprotein convertases in tumorigenesis has been extensively reviewed. 2, 13, 14 Some of the cleaved protein precursors by the PCs, such as matrix metalloproteases, adhesion molecules, growth factors, and growth factor receptors are directly or indirectly involved in tumorigenesis and metastasis by regulating either degradation of extra-cellular matrix and/or modulation of cell growth and survival. 2, 13, 14 Using different tumor cells with invasive/metastatic phenotypes, the inhibition of PC-activity was found to provoke dramatic changes in several phenotypes that impact on the metastatic potential of tumor cells. 2, 13, 14 Similarly, using various sitedirected mutagenesis, we found that the inhibition of the processing of several PC substrates such as PDGF-A, 15 and VEGF-C 16 reduced significantly their ability to induce tumor development and angiogenesis, respectively. 15, 16 This data highlighted the importance of PCs in the activation of these growth factors during tumor progression and angiogenesis. 15, 16 C. Bacterial Toxins Activation by the PCs Three different classes of bacterial toxins were described to be activated by the PCs. The toxins of the first class are synthesized as single polypeptide chains that group the toxic subunit and the target binding subunit. The toxin precursors are cleaved during their interaction with the target cell surface or in the endosomal compartment by the PCs. [17] [18] [19] [20] Of the toxins that belong to this class and were reported to be activated by the PCs are the Diptheria toxin, 19 Pseudomonas aeruginosa exotoxin A (PEA), 17, 18 Botulinum neurotoxin, and Bordetella dermonecrotic toxin. 20 The second class of toxins such as Anthrax are synthesized as separate polypeptide chains and usually assemble on the target cell surface to form the active toxin following activation of the binding subunit by the PCs. 21, 22 The third class groups the pore-forming toxins such as the aerolysin. These toxins are produced and secreted as a dimer that bind on target cells to the glycosylphosphatidyl inositol anchors of membrane proteins. Usually the cleavage of these toxins by the PCs occurred on the surface of the target cell during their binding. This process seems to be crucial for the association of the toxin dimers into heptamer pore complex and causes cell lysis. 23 

Previously, data on various infectious viruses revealed that the cleavage of their envelope glycoprotein precursors by one or more PC is a required step for the acquisition of the infectious capacity of viral particles. Indeed, various studies demonstrated the capacity of the PCs to correctly cleave a variety of viral surface glycoproteins. These include the HIV-1 gp160 24, 25 and surface glycoproteins of Hong Kong, Ebola virus, and the severe acute respiratory syndrome coronavirus. 26, 27 In parallel, other studies revealed that the inhibition of processing of these viral surface glycoproteins by the PC inhibitors such as dec-R-V-K-R-CMK completely abrogated the virus-induced cellular cytopathicity. Recently, the surface glycoproteins of other viruses, particularly the hemorrhagic fever viruses (Arenaviridae family) such as Lassa, 28, 29 Crimean Congo hemorrhagic fever, 30 and lymphocytic choriomeningitis 31 were shown to be cleaved by the convertase SKI-1. Similarly, blockade of SKI-1 activity by specific inhibitor were also shown to affect the processing and the stability of the glycoproteins of these viruses. 32 

Since the discovery of Furin, the growing evidence of PCs implication in various pathological processes made these enzymes important potential therapeutic targets. Thereby various attempts have been made to develop specific and potent inhibitors to target these enzymes. All the inhibitors that were found or developed so far are grouped into natural endogenous or exogenous PC inhibitors.

To date the only naturally occurring intracellular PC inhibitors found in the constitutive secretory pathway are PCs own propeptides or prosegments. 33, 34 Previously, it was reported that many proteins use their propeptides as intramolecular chaperones for their correct folding, transport, and/or secretion. 35 In addition to these prosegment functions, these enzyme fragments were also reported to act as inhibitors for various enzymes including the PCs. 2, 33, 34 Like their substrates the PCs are synthesized as inactive proenzymes and are auto-catalytically activated. [1] [2] [3] [4] [5] [6] 36 Following their signal sequence removal and endoplasmic reticulum (ER) folding events, PCs undergo auto-proteolytic cleavage of their prosegment at R107 (Fig. 1 ). The prosegment, however, remains associated with the mature domain of the enzyme and functions as a potent auto-inhibitor during transport to the late secretory pathway. After this step, the inactive complex transits to the late trans-Golgi network (TGN) where the relatively acidic pH permits a second autoproteolytic cleavage of the prosegment at R75 and activates the convertase (Fig. 1 ). 6, 35 Using these inhibitors, we were able to inhibit the processing and the function of various PC substrates such as PDGF-A, 15 PDGF-B, 37 VEGF-C, 16 and IGF-1 receptor 2 (Fig. 2) . Recently, the Furin inhibition by its pro-segment proFurin was reported as feasible approach to reduce and/or abolish the malignant phenotype of various malignancies. 38 Indeed, the expression of the complete proFurin cDNA sequence in various human head and neck squamous cell carcinoma cell lines was found to reduce dramatically their proliferation, tumorigenicity, and invasiveness in vitro and in vivo as well. 38 These proFurin effects were directly linked to the inhibition of Furin-mediated activation of various crucial cancer-related substrates, such as TGF-b, VEGF-C, IGF-1 receptor, and MT1-MMP. 38 

Little is known about the cellular function of 7B2. Nevertheless, Braks and Martens were the firsts to show that 7B2 act as a chaperone for proPC2 and be able to bound to the latter in the early compartment of the secretory pathway and dissociates from it in the latter ones. 39 Other studies proposed that 7B2 may also facilitates proPC2 transport from the endoplasmic reticulum to the secretory granules and participates in the generation of fully active PC2. 40 Following their secretion, pro7B2 and proPC2 interact in the ER in the presence of an alkaline pH and form an inactive complex (pro7B2-proPC2). During its progression through the TGN in the presence of decreased pH and increased [Ca 2þ ] the pro7B2 is cleaved by the PCs and released a C-terminal fragment with inhibitory function on PC2. 41, 42 In the secretory granules, additional pH decreases and [Ca 2þ ] increases permits proPC2 self activation and liberates the prodomain of PC2 that provides a fully active PC2 (Fig. 3) . Subsequently, the N-terminal domain of PC2 and C-terminal domain of 7B2 are rapidly degraded by PC2 and carboxypeptidase E (Fig. 3) . [40] [41] [42] 3. ProSAAS; the Naturally Occurring Inhibitor of PC1 Like 7B2, ProSAAS, contains an N-terminal and a C-terminal domain that are separated by a PC cleavage sites. The sequence responsible for the inhibitory potency of PC1 was previously pointed to the hexapeptide, L-L-R-V-K-R, located in the proSAAS C-terminal domain. 43 This peptide was identified by combinatorial library peptide screening as a tight binding site for PC1. 44, 45 Like PC2, PC1 is inactive in the endoplasmic reticulum and Golgi apparatus due to the neutral pH and relatively low Ca 2þ levels in addition to its interaction with proSAAS. 46 Following its progression through the TGN, proSAAS is cleaved into two peptides designed as PEN and LEN fragments that remove the inhibition of PC1 by proSAAS (Fig. 4) . 

Inter-alpha-inhibitor protein (IalphaIp) is an abundant endogenous serine protease inhibitor initially isolated from human plasma. [47] [48] [49] [50] IalphaIp consists of three polypeptides: two heavy chains and one light chain called bikunin. Analysis of the bikunin structure revealed the presence of two protease domains of the Kunitz type carrying the antiproteolytic function of the IalphaIp. Bikunin was found to be effective against a broad range of enzymes that includes trypsin, chymotrypsin, plasmin, and leukocyte elastase, as well as cathepsins B and H. [46] [47] [48] [49] Although crystal structure analysis of bikunin revealed direct interaction between trypsin and the two domains of bikunin, the inhibitory mechanism of IalphaIp remain unknown. 48 Recently, the IalphaIp was also proposed as a good inhibitor for the Furin to prevent the formation of active anthrax lethal toxin. 51 Indeed, this inhibitor was able to provide significant protection against cytotoxicity for murine peritoneal macrophages exposed to high doses of the anthrax lethal toxin 51 (Fig. 5) .

Initial studies indicated that the serpin proteinase inhibitor 8 (PI8) was able to inhibit a variety of proteinases through different mechanisms. This inhibitor was shown to inactivate the porcine trypsin, human thrombin, human coagulation factor Xa, and the Bacillus subtilis dibasic endoproteinase subtilisin A. 52 This 45-kDa serpin was reported to form a SDS-stable complex with human Furin and provoke the inhibition of the enzyme. The PI8-mediated Furin inhibition is due to the presence in the reactive site domain of the inhibitor a PC cleavage sites namely R-N-S-R339 and R-C-S-R342. 53 

Most exogenous inhibitors of the proprotein convertases were generated to act in a competitive fashion. Most of these inhibitors contain the general cleavage motif of the PCs (K/R) À (X) n À (K/R)#. In the presence of alkaline pH and a poor environment, the free ProPC2 interact with Pro7B2 to form an inactive complex pro7B2-proPC2. Through its progression in the trans-Golgi network (TGN) where the pH is decreased and the [Ca 2þ ] is increased, pro7B2 is cleaved by the PC and the C-terminal fragment of 7B2 remained attached to proPC2. In the secretory granule (SG), where the pH is lower and the [Ca 2þ ] is higher, the proPC2 is cleaved auto-catalytically to liberate the prodomain fragment. The N-terminal domain of PC2 and the C-terminal and N-terminal domains of 7B2 are rapidly degraded by PC2 and carboxypeptidase E and generates a fully activated PC2.

These synthetic inhibitors contain in their structures an acyl moiety that allows them to enter into the cells and bind to the active site of the PCs through its peptidyl group. 54 They were the first compounds that were demonstrated to inhibit the PCs. 55 Of the members of this family the derivative decanoyl-R-V-L-R-chloromethylketone was found to inhibit various PCs substrates ranging from growth factors to viral glycoproteins. 55 This inhibitor was previously used to inhibit the activity of various MMPs and tumor cell invasion processes. 56, 57 Similarly, treatment of a prostate cancer cell line with this reagent was found to inhibit the processing of prostate-derived factor (PDF) and other members of the TGF-b superfamily that was associated with a loss of prostate cancer cell differentiation. 58 

Recently the poly-arginines were also described as potent inhibitors of the PCs. [59] [60] [61] Based on the reported structure of mouse Furin the active site of the enzyme seems to contain an extended substrate-binding groove that is lined with many negatively charged residues. 60 Thereby the highly acidic character of the substrate-binding groove explains the high-inhibitory potency of positively charged polyarginine-containing peptides. [59] [60] [61] Recently, the hexa-D-arginine amide was found to inhibit significantly the Pseudomonas aeruginosa exotoxin A (PEA) processing and PEA-induced toxicity in mice. 61 Also the polyarginine inhibitors were reported to be able to inhibit the processing of the human immunodeficiency virus-1 gp160 and the replication of the virus as well. 62 

Turkey ovomucoid third domain with normal reactive site is known as a potent inhibitor of various serine proteinases including subtilisins, chymotrypsins, and elastases. 63 Mutation of this inhibitor at L18K in its reactive site made it a strong inhibitor of trypsin and its mutation at the same site into L18E made it a strong inhibitor of Glu-specific streptomyces griseus proteinase (GluSGP) 64 (Fig. 6) . In parallel, the introduction of a proprotein convertases site its structure made it a moderate Furin inhibitor 65 (Fig. 6) . 

Eglin C is a proteinase inhibitor that strongly inhibits human leukocyte elastase, cathepsin G, achymotrypsin, and substilisin. 66 This inhibitor was initially isolated from the leech Hirudo medicinalis and belongs to the potato I inhibitor family. 67 Previously, it was reported that its inhibitory specificity could be changed and inhibits trypsin by a point mutation at its reactive site L45R. Subsequently, substitution of residues at each position P1, P2, and P4 of eglin C with a basic residue made it a very strong inhibitor for Furin. 68 Recently, the generation of the three-dimensional complex structures of Furin-eglin C mutant interaction by a modeller program provided crucial information on the interaction between the Furin and this inhibitor. 69 The modellation of this interaction allowed the calculation of the electrostatic interaction energies between the Furin and eglin C mutant. 69 The results that were obtained from this study highlighted the importance of the charge-charge interactions in the binding of Furin to its inhibitors, suggesting the roles of the electrostatic interactions in the inhibitory activity of eglin C mutant toward Furin. 69 Further analysis revealed that the mutation of R48D (P3 0 residue) in eglin C seems to increase the inhibitory action of the eglin C mutant due to the electrostatic interactions of D48 with R86 and R90 of Furin (Fig. 7) . The discovery of this inhibitor was initially based on the observation previously reported for a patient with a mutation in its a1-antitrypsin. 70 This patient was shown to be unable to cleave the pro-albumin at the Furin consensus site. 71 This variant of a1-antitrypsin, called a1-anti-trypsin Pittsburgh (PIT), has a replacement of the reactive-site M358 residue by R358 residue. Subsequently, the group of G. Thomas developed another variant of a1-antitrypsin, called a1-anti-trypsin Portland (a1-PDX), in which the reactive-site A-I-P-M has been replaced by R-I-P-R. This serpin was revealed to inhibit Furin with a Ki of 600 pM, three times lower than the PIT inhibitor. 72 Subsequently, kinetic analysis showed that a portion of bound a1-PDX operates as a suicide inhibitor (Fig. 8) . Once bound to Furin's active site, a1-PDX can either undergo proteolysis by Furin or form a kinetically trapped SDS-stable complex with the enzyme. 73 Furthermore, when expressed in cells, a1-PDX was shown to be a potent inhibitor of Furin-mediated cleavage of HIV gp 160, 72 and subsequently demonstrated to inhibit all PCs involved in processing within the constitutive secretory pathway. In vitro experiments revealed also its ability to block the processing of various proteins related tumor progression and metastasis such as several growth factors (Fig. 2) , receptors, various MMPs and adhesion molecules. [1] [2] [3] [4] [5] [6] 13, 15, 16 

These synthetic peptides were designed and developed from the reactive site loop of the PC inhibitor a1-PDX in a way to contain the PC cleavage motif R-I-P-R382. 74 To make a circular peptide a Cys residue was inserted at each terminal residue of several mini-PDX peptides. In vitro digestion analysis in the presence of various synthetic PC substrates revealed that the mini-PDX is able to inhibit in vitro Furin activity in a slow tight-binding manner. Contrary to the PCs inhibitor a1-PDX, these synthetic peptides seem to inhibit Furin via a different mechanistic pathway that required further investigations. 74 

Human a2-macroglobulin is a homotetrameric glycoprotein present at high concentrations in the blood. Each monomeric subunit contains an internal S-ester (ISE). a2-macroglobulin inhibits a wide range of proteases by a unique mechanism. 75 Inhibition is initiated by cleavage of a flexible and surface-accessible peptide stretch called the bait region (Fig. 9 ). This cleavage triggers the hydrolysis of the ISEs, followed by a major conformational change. The protease becomes ''trapped'' by the inhibitor and is thus sterically shielded from its substrate. 75 By introducing a Furin recognition sequence in the bait region of a2-macroglobulin, Van Rompaey et al., have generated a potent PC inhibitor as revealed by its ability to inhibit the processing of von Willebrand factor, TGF-b1, and the HIV-1 glycoprotein gp160. 76 Lately, it was revealed that the mutation introduced in the bait region of a2-macroglobulin did not interfere neither with folding, neither on tetramerization of the inhibitor. Also the Furin inhibition mechanism by this a2-macroglobulin mutant was found to be similar to those used for the inhibition of other proteases by a2-macroglobulin 76 (Fig. 9 ).

Diterpines are the first reported nonprotein inhibitor of Furin. 77 These neoandrographolide, are extracted from the medicinally active plant Andrographis paniculata, and are succinoyl ester derivatives 77 (Fig. 10) . The actual mechanism by which these diterpines exert their inhibitory effects against PC is not clearly understood. Nevertheless, these molecules contain a very reactive fivemembered lactone ring that was found in several elastases inhibitors, suggesting the potential role of this lactone ring in the Furin activity inhibition. Although the in vitro inhibition is relatively weak, these compounds seem to penetrate more easily in the cell and might enhance their inhibitory potential in vivo.

These compounds were recently shown to have an interesting degree of convertases selectivity. 78 This new class of nonpeptide inhibitor consists of an ion Cu 2þ or Zn 2þ coupled with a chelator compound (Fig. 11) . The inhibition of the Furin by these compounds is irreversible and the inhibitor binds at the enzyme active site of the enzyme. Indeed, analysis of Furin sequence revealed the presence in its active site residues being able to bind divalent zinc and copper. This includes the catalytic H194, C198, and H364. 78 

Over the last 15 years, the cumulative knowledge revealed the implication of the proprotein convertases in various disorders including diabetes, atherosclerosis, cancer, familial hypercholesterolemia, viral infections, and Alzheimer disease. Thereby, the use of general PC inhibitors is now suggested to be advantageous and could be a promising therapeutic strategy. However, in some cases it may be necessary to target only one member of the PC family. This is feasible, as was demonstrated previously for pro-SAAS and 7B2. In addition the recently published crystal structures of the Furin will undoubtedly help for the search, design, and the development of specific and potent inhibitor for each PC. Indeed, the availability of the crystal structures of the Furin has recently revealed precious knowledge on the characteristics of the other PCs through modellation of their structures. 60 Based on these studies, the arrangement of the catalytic and P domains, and the architecture of the substrate binding clefts of the Furin seems to be more similar to those of PC4, PACE4, and PC5/6, and less similar to those of PC1/3, PC2, and PC7. 60 Following their development these specific inhibitor could be used alone or in combination to target PC-mediated diseases. Recent studies revealed that small molecule proprotein convertases inhibitors are the most attractive potential therapeutic agents. However, only the diterpene and several Cu and Zn chelators where reported as nonpeptide PC inhibitors. Although these inhibitors were able to inhibit the activity of the PCs in vitro, their ability to block the processing of various PC substrates in vivo is not yet tested. Similarly, to improve the specificity and the efficacy of such inhibitors, chemical modifications of their structures followed by structure-activity studies are required. In the long term, the potential developed specific and potent PC inhibitors may provide a rationale for testing this family of compounds as therapeutic agents or in conjunction with standard therapy in clinical settings.

This work was supported by the Fondation pour la Recherche Médicale and Avenir Award, Paris, France.

Proprotein and prohormone convertases: A family of subtilases generating diverse bioactive polypeptides

Proprotein convertases in tumor progression and malignancy: Novel targets in cancer therapy

Curbing activation: Proprotein convertases in homeostasis and pathology

The proprotein convertases

Proteolytic processing in the secretory pathway

Furin at the cutting edge: From protein traffic to embryogenesis and disease

Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization

Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells

The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation

Functional characterization of Narc 1, a novel proteinase related to proteinase K

Processing of beta-secretase by furin and other members of the proprotein convertase family

A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta-secretase

Endo/exo-proteolysis in neoplastic progression and metastasis

Role of subtilisin-like convertases in cadherin processing or the conundrum to stall cadherin function by convertase inhibitors in cancer therapy

The proteolytic processing of pro-plateletderived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity

The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis

Reduction of furin-nicked Pseudomonas exotoxin A: An unfolding story

Expression of mouse furin in a Chinese hamster cell resistant to Pseudomonas exotoxin A and viruses complements the genetic lesion

Proteolytic activation of bacterial toxins by eukaryotic cells is performed by furin and by additional cellular proteases

Bordetella dermonecrotic toxin exerting toxicity through activation of the small GTPase Rho

Proteolytic activation of receptor-bound anthrax protective antigen on macrophages promotes its internalization

A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen

Van der Goot FG. The pore-forming toxin proaerolysin is activated by furin

Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(þ) cell lines

Processing and routage of HIV glycoproteins by furin to the cell surface

Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses: A comparative analysis with fluorogenic peptides

Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P

A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus

Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1

Endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase SKI-1/S1P

Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: Processing of SREBP-2, ATF6, and a viral glycoprotein

Proprotein convertase PC1/3-related peptides are potent slow tightbinding inhibitors of murine PC1/3 and Hfurin

The prosegments of furin and PC7 as potent inhibitors of proprotein convertases In vitro and ex vivo assessment of their efficacy and selectivity

Propeptide mediated protein folding: Intramolecular chaperones

The mammalian family of subtilisin/kexin-like pro-protein convertases

The ordered and compartment-specfific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin

7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway

7B2 facilitates the maturation of proPC2 in neuroendocrine cells and is required for the expression of enzymatic activity

The neuroendocrine polypeptide 7B2 is an endogenous inhibitor of prohormone convertase PC2

Dissociation of the complex between the neuroendocrine chaperone 7B2 and prohormone convertase PC2 is not associated with proPC2 maturation

The SAAS granin exhibits structural and functional homology to 7B2 and contains a highly potent hexapeptide inhibitor of PC1

Identification of inhibitors of prohormone convertases 1 and 2 using a peptide combinatorial library

Identification and characterization of proSAAS, a graninlike neuroendocrine peptide precursor that inhibits prohormone processing

The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1

The inter-alpha-inhibitor family: From structure to regulation

Bikunin-Not just a plasma proteinase inhibitor

Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis

The crystal structure of bikunin from the inter-alpha-inhibitor complex: A serine protease inhibitor with two Kunitz domains

Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication

Expression, purification, and inhibitory properties of human proteinase inhibitor

Inhibition of soluble recombinant furin by human proteinase inhibitor 8

Synthesis of oligopeptide chloromethanes to investigate extended binding regions of proteinases: Application to the interaction of fibrinogen with thrombin

Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160

Activated isoforms of MMP-2 are induced in U87 human glioma cells in response to beta-amyloid peptide

BCL-2-induced glioma cell invasiveness depends on furin-like proteases

Proprotein convertases regulate activity of prostate epithelial cell differentiation markers and are modulated in human prostate cancer cells

Polyarginines are potent furin inhibitors

Proprotein convertase models based on the crystal structures of furin and kexin: Explanation of their specificity

The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin A in vivo

Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection

Thermodynamics and kinetics of single residue replacements in avian ovomucoid third domains: Effect on inhibitor interactions with serine proteinases

Replacement of P1 Leu18 by Glu18 in the reactive site of turkey ovomucoid third domain converts it into a strong inhibitor of Glu-specific Streptomyces griseus proteinase (GluSGP)

Arg15-Lys17-Arg18 turkey ovomucoid third domain inhibits human furin

Binding of the recombinant proteinase inhibitor eglin c from leech Hirudo medicinalis to human leukocyte elastase, bovine alphachymotrypsin and subtilisin Carlsberg: Thermodynamic study

Structure of the elastase-cathepsin G inhibitor of the leech Hirudo medicinalis

Two engineered eglin c mutants potently and selectively inhibiting kexin or furin

Rational redesign of inhibitors of furin/kexin processing proteases by electrostatic mutations

Mutation of antitrypsin to antithrombin alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder

Circulating proalbumin associated with a variant proteinase inhibitor

Inhibition of HIV-1 gp160-dependent membrane fusion by a furin-directed alpha 1-antitrypsin variant

Serpin-like properties of alpha1-antitrypsin Portland towards furin convertase

Modulating furin activity with designed mini-PDX peptides: Synthesis and in vitro kinetic evaluation

The interaction of alpha 2-macroglobulin with proteinases Characteristics and specificity of the reaction, and a hypothesis concerning its molecular mechanism

Inhibition of intracellular proteolytic processing of soluble proproteins by an engineered alpha 2-macroglobulin containing a furin recognition sequence in the bait region

Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters

Furin inhibition by compounds of copper and zinc

Now he is a post-Ph.D. in oncology at the INSERM institute U716/Avenir. Actually, his researches focused on the importance of two recently discovered convertases (Narc-1 and Ski-1) in health and disease

Nathalie Scamuffa has worked few years as an engineer in genetics at the University of Medicine of Geneva

He is a professor of pharmacology at the Paris 7 School of medicine and head of the INSERM U716 at Saint Louis Hospital. His research interests are new targets for anticancers drug development both in the preclinical and clinical settings

Abdel Majid Khatib obtained his Ph.D. in cell and molecular biology from the University of Paris. As a scientist, he first joined the University of Ottawa. He is now working at the INSERM institute U716/Avenir. His research interests are dealing with the role of proteins maturation by the convertases in health and disease