Novel Insights into Structure–Activity Relationships of N‐Terminally Modified PACE4 Inhibitors

Kwiatkowska, Anna; Couture, Frédéric; Lévesque, Christine; Ly, Kévin; Beauchemin, Sophie; Desjardins, Roxane; Neugebauer, Witold; Dory, Yves L.; Day, Robert

doi:10.1002/cmdc.201500532

Cited by 14 publications

(49 citation statements)

References 38 publications

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“…Besides the elongation with basic residues, compounds with an N‐terminal acetylated multi‐Leu motif were prepared as references, which were described in previous work by the Day research group . Inhibitors 18 and 19 were resynthesized, their K i values of ≈0.5 n m determined in our assay are approximately 10‐ and 20‐fold lower than the inhibition constants described by Kwiatkowska et al . These discrepancies are probably caused by different assay conditions.…”

Section: Discussionmentioning

confidence: 86%

“…Based on the work of the Day research group, inhibitors containing an N‐terminal tetra‐Leu motif including the previously described inhibitors 18 and 19 were synthesized as further reference compounds . Under the used conditions derivative 18 (Ac‐(Leu) 4 ‐Arg‐Val‐Lys‐4‐Amba) and its N‐terminal Ac‐ d Leu analogue 19 inhibit furin with nearly identical K i values of 491 and 449 p m , respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The effective inhibition of furin represents a potential strategy for a short‐time treatment of numerous severe infectious diseases . So far, the most potent synthetic inhibitors of furin and furin‐like PCs contain a C‐terminal 4‐amidinobenzylamide residue . It was known that the incorporation of a basic P5 anchor strongly improves the affinity of this inhibitor type .…”

Section: Discussionmentioning

confidence: 99%

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Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

et al. 2017

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Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacteyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, e.g., Nα(carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki = 6.2 pM), contain additional basic residues at the N-terminus and inhibit furin in the low picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds lacking the P5-moiety were prepared. The best inhibitors of this series, 5-(guanidino)-valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert.leucine analogue, displayed Ki values of 2.50 nM and 1.26 nM, respectively. Selected inhibitors, together with our previously described 4-amidinobenzylamide derivatives as references, were tested in cell culture for their activity against furin-dependent infectious pathogens. The propagation of the alphaviruses Semliki Forest virus and chikungunya was strongly inhibited in the presence of selected derivatives. Moreover, a significant protective effect of the inhibitors against diphtheria toxin was observed. These results confirm that the inhibition of furin should represent a promising approach for a short-term treatment of acute infectious diseases.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

et al. 2017

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“…On the other hand, the higher hydrophobicity prohibits binding to furin. In fact, this inhibitor has proved to bind PACE4 with Ki in the nM range and about twenty times lower than furin, and is an efficient inhibitor of cancer cell proliferation [60, 61]. …”

Section: Paralyzing the Master Switches: Inhibition Of Pcsmentioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents has also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.

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“…The 4‐Amba residue has also been used for the design of N‐terminally elongated furin and PACE4 inhibitors by the Day group . However, increased toxicity was found for these derivatives compared with analogues containing an Arg‐amide or 2,3‐dehydroagmatine as P1 groups.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Substrate‐Analogue Furin Inhibitors

et al. 2017

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The proprotein convertase furin is a potential target for drug design, especially for the inhibition of furin-dependent virus replication. All effective synthetic furin inhibitors identified thus far are multibasic compounds; the highest potency was found for our previously developed inhibitor 4-(guanidinomethyl)phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). An initial study in mice revealed a narrow therapeutic range for this tetrabasic compound, while significantly reduced toxicity was observed for some tribasic analogues. This suggests that the toxicity depends at least to some extent on the overall multibasic character of this inhibitor. Therefore, in a first approach, the C-terminal benzamidine of MI-1148 was replaced by less basic P1 residues. Despite decreased potency, a few compounds still inhibit furin in the low nanomolar range, but display negligible efficacy in cells. In a second approach, the P2 arginine was replaced by lysine; compared to MI-1148, this furin inhibitor has slightly decreased potency, but exhibits similar antiviral activity against West Nile and Dengue virus in cell culture and decreased toxicity in mice. These results provide a promising starting point for the development of efficacious and well-tolerated furin inhibitors.

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Novel Insights into Structure–Activity Relationships of N‐Terminally Modified PACE4 Inhibitors

Cited by 14 publications

References 38 publications

Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Optimization of Substrate‐Analogue Furin Inhibitors

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