Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors

Weigel, Lena F.; Nitsche, Christoph; Graf, Dominik; Bartenschlager, Ralf; Klein, Christian D.

doi:10.1021/acs.jmedchem.5b00612

Cited by 76 publications

(60 citation statements)

References 60 publications

(141 reference statements)

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“…Numerous studies have focused on the development of protease inhibitors derived from a substrate-mimicking peptide. Strategies included incorporation of a carboxyterminal electrophile 52,54,[73][74][75] , optimization of the N-terminal capping moiety 53,56,76,77 , and modulation of the P 1 and P 2 basic residues through non-natural building blocks 53,78 . Aldehydic inhibitors displayed low micromolar to nanomolar affinity for DENV serotype 2 (DENV-2) 74 and WNV 52,75 proteases.…”

Section: Ns3 Protease Inhibitorsmentioning

confidence: 99%

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Boldescu

Behnam

Vasilakis³

et al. 2017

Nat Rev Drug Discov

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Infections with flaviviruses, such as dengue, West Nile virus, and the recently re-emerging Zika virus are an increasing and probably lasting global risk. This review summarizes and comments on the opportunities for broad-spectrum agents that are active against a range of flaviviruses. Broad-spectrum activity would be particularly desirable as preparatory measure for the next flaviviral epidemic that could emerge from as-yet-unknown or neglected viruses. Potential target sites for broad-spectrum anti-flaviviral compounds include viral proteins and host mechanisms that are exploited by these viruses during entry and replication. A variety of compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For some other compound classes, broad-spectrum activity can be anticipated because of their mode of action and molecular target(s).

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Section: Ns3 Protease Inhibitorsmentioning

confidence: 99%

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Boldescu

Behnam

Vasilakis³

et al. 2017

Nat Rev Drug Discov

Self Cite

249

217

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“…The permeability was evaluated as reported, using a pre-coated PAMPA plate system (BD Gentest, BD Bioscience, Germany). 11 Phosphate buffered saline (PBS) pH 7.4 (Sigma-Aldrich, Germany)…”

Section: S17mentioning

confidence: 99%

A New Class of Dengue and West Nile Virus Protease Inhibitors with Submicromolar Activity in Reporter Gene DENV-2 Protease and Viral Replication Assays

et al. 2020

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Dengue and West Nile virus are rapidly spreading global pathogens for which no specific therapeutic treatments are available. One of the promising targets for drug discovery against dengue and other flaviviruses is the viral serine protease NS2B-NS3. We present the design, synthesis, and in vitro and cellular characterization of a novel chemotype of potent small-molecule non-peptidic dengue protease inhibitors derived from 4-benzyloxyphenylglycine. A newly developed luciferase-based DENV-2 protease reporter system in HeLa cells (DENV2proHeLa) was employed to determine the activity of the compounds in a cellular environment. Specificity and selectivity of the DENV2proHeLa system were confirmed by viral titer reduction assays. The compounds reach low micromolar to upper nanomolar inhibitory potency in cell-based assays, are selective against other serine proteases, and do not show relevant cytotoxicity. An extensive structure–activity relationship study provides a perspective for further drug development against flaviviral infections.

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“…Proteinogenic amino acids do not contain substituents, which additionally increase the acidity of the α-proton. Nevertheless, glycine derivatives with electron-withdrawing substituents like formylglycine [ 58 – 59 ], phenylglycine [ 60 – 61 ] and fluorinated alanine [ 62 – 64 ] have attracted great attention as peptidomimetics, drugs or in the bioorthogonal functionalization of larger peptides.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

Wünsch

Schröder

Fröhr

et al. 2017

Beilstein J. Org. Chem.

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The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.

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Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors

Cited by 76 publications

References 60 publications

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

A New Class of Dengue and West Nile Virus Protease Inhibitors with Submicromolar Activity in Reporter Gene DENV-2 Protease and Viral Replication Assays

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

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