Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells

Lu, Yinghui; Hardes, Kornelia; Dahms, S.O.; Böttcher‐Friebertshäuser, Eva; Steinmetzer, Torsten; Than, Manuel E.; Klenk, Hans‐Dieter; Garten, Wolfgang

doi:10.1016/j.antiviral.2015.05.006

Cited by 32 publications

(27 citation statements)

References 74 publications

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“…The hemagglutinin precursor HA0 is cleaved by furin into HA1 and HA2. Results obtained with this screening assay usually correlate well with the antiviral activity of inhibitors in cell‐based infection studies as shown previously for H7N1 and H5N1 HPAIV, canine distemper virus, Semliki Forest virus, chikungunya virus, West Nile virus, and Dengue‐2 virus . In the current study, strong differences in potency were found in this assay, as shown by the Western blot in Figure .…”

Section: Resultssupporting

confidence: 87%

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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Section: Resultssupporting

confidence: 87%

Optimization of Substrate‐Analogue Furin Inhibitors

et al. 2017

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“…In previous cell culture experiments, we have observed that selected 4‐amidinobenzylamide‐type furin inhibitors exhibit strong antiviral activity against highly pathogenic avian influenza viruses of the strains H5N1 and H7N1 as well as against canine distemper virus . Furthermore, these compounds strongly protected cells against anthrax, Shiga and diphtheria toxin in cell culture .…”

Section: Resultsmentioning

confidence: 97%

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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“…The PCs are also involved in a large number of pathologies, including bacterial and viral infections, as well as cancer and metastasis. Therefore, these enzymes are intensely investigated as drug targets (3), using for example, peptide-derived compounds (4)(5)(6)(7)(8)(9), nonpeptidic small molecule compounds (10,11), and protein-based inhibitors (12)(13)(14)(15).…”

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Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism

Dahms

Arciniega

Steinmetzer

et al. 2016

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

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Proprotein convertases (PCs) are highly specific proteases required for the proteolytic modification of many secreted proteins. An unbalanced activity of these enzymes is connected to pathologies like cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Novel protein crystallographic structures of the prototypical PC family member furin in different functional states were determined to 1.8-2.0 Å. These, together with biochemical data and modeling by molecular dynamics calculations, suggest essential elements underlying its unusually high substrate specificity. Furin shows a complex activation mechanism and exists in at least four defined states: (i) the "off state," incompatible with substrate binding as seen in the unliganded enzyme; (ii) the active "on state" seen in inhibitor-bound furin; and the respective (iii) calcium-free and (iv) calcium-bound forms. The transition from the off to the on state is triggered by ligand binding at subsites S1 to S4 and appears to underlie the preferential recognition of the four-residue sequence motif of furin. The molecular dynamics simulations of the four structural states reflect the experimental observations in general and provide approximations of the respective stabilities. Ligation by calcium at the PC-specific binding site II influences the active-site geometry and determines the rotamer state of the oxyanion holeforming Asn295, and thus adds a second level of the activity modulation of furin. The described crystal forms and the observations of different defined functional states may foster the development of new tools and strategies for pharmacological intervention targeting furin.serine-protease | activation | specificity | conformational transition

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Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells

Cited by 32 publications

References 74 publications

Optimization of Substrate‐Analogue Furin Inhibitors

Optimization of Substrate‐Analogue Furin Inhibitors

Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism

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