Thiazolidone derivatives as inhibitors of chikungunya virus

Jadav, Surender Singh; Sinha, Barij Nayan; Hilgenfeld, Rolf; Pastorino, Boris; Lamballerie, Xavier de; Jayaprakash, Venkatesan

doi:10.1016/j.ejmech.2014.10.042

Cited by 52 publications

(55 citation statements)

References 34 publications

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“…The crystal structure of CHIKV nsP2 protease was obtained from the Protein Data Bank (PDB code 3RTK). The hydrophobic hydrogen atoms were added to the structure for further modeling (37), and docking was performed essentially as previously described (30). In docking simulations, the nsP2 protein was kept as a rigid molecule.…”

Section: Methodsmentioning

confidence: 99%

“…This docking site is similar to that used in several previous studies. Thus, in modeling the thiazolidone derivates as CHIKV nsP2 protease inhibitors, the most important binding amino acid residue was found to be Tyr1047 (30), while in another study by the same group, residues Tyr1047, Trp1084, and Asp1246 were determined as the most important ones (38). Similarly, Bassetto and coworkers (32) described the docking pose of inhibitors with the enzyme residues His1083, Cys1013, Asn1082, and Trp1084.…”

Section: Molecular Designmentioning

confidence: 99%

“…This region is folded similarly in nsP2s of different alphaviruses and thus represents a potential target both for specific and pan-alphavirus protease inhibitors. Virtual screening in the ZINC database using the Glide module by Schrödinger LLC has been carried out (28)(29)(30). Molecular docking was carried out using the hypothetical CHIKV nsP2 protease active site in the area of the catalytic amino acid residues Cys1013, His1083, and Trp1084 (here and below, the amino acid residues are numbered from the N terminus of P1234).…”

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confidence: 99%

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Design and Validation of Novel Chikungunya Virus Protease Inhibitors

Das

Puusepp

Varghese

et al. 2016

Antimicrob Agents Chemother

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dChikungunya virus (CHIKV; genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast, there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2. The available three-dimensional (3D) structure of nsP2 protease has made it a target for in silico drug design; however, there is thus far little evidence that the designed compounds indeed inhibit the protease activity of nsP2 and/or suppress CHIKV replication. In this study, a set of 12 compounds, predicted to interact with the active center of nsP2 protease, was designed using target-based modeling. The majority of these compounds were shown to inhibit the ability of nsP2 to process recombinant protein and synthetic peptide substrates. Furthermore, all compounds found to be active in these cell-free assays also suppressed CHIKV replication in cell culture, the 50% effective concentration (EC 50 ) of the most potent inhibitor being ϳ1.5 M. Analysis of stereoisomers of one compound revealed that inhibition of both the nsP2 protease activity and CHIKV replication depended on the conformation of the inhibitor. Combining the data obtained from different assays also indicates that some of the analyzed compounds may suppress CHIKV replication using more than one mechanism. C hikungunya virus (CHIKV; genus Alphavirus, family Togaviridae) is the causative agent of chikungunya fever, a disease that has affected millions in the last decade. It is characterized by high fever, arthralgia, myalgia, headache, and rash. The disease is usually self-limiting; however long-lasting chronic symptoms are observed in nearly 50% of CHIKV-infected patients (1). As there is no approved vaccine or specific licensed antiviral compounds (2), the treatment of CHIKV infection is largely based on relief of symptoms.CHIKV infection can be inhibited by targeting host factors essential for virus infection. Targeting of several metabolic pathways has revealed anti-CHIKV effects of several licensed drugs (3). Compounds most likely targeting virus entry or host cell-specific components required for virus infection have been described (4-8). Several nucleosides or nucleotides, acting as pseudosubstrates for CHIKV RNA-dependent RNA polymerase and/or using another, more general mechanism of action, have shown anti-CHIKV activity (9). In addition, anti-CHIKV effects have been described for several groups of novel synthetic compounds (10-12).Computer-aided design based on molecular docking and molecular dynamics simulations and pharmacophore approach allows identifying potential in silico hits as active inhibitors for different CHIKV replicase proteins. This approach, however, requires the three-dimensional (3D) structure...

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Section: Methodsmentioning

confidence: 99%

Section: Molecular Designmentioning

confidence: 99%

mentioning

confidence: 99%

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Design and Validation of Novel Chikungunya Virus Protease Inhibitors

Das

Puusepp

Varghese

et al. 2016

Antimicrob Agents Chemother

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“…In addition to the catalytic Cys, Asn475 and Lys480 residues (correspond to residues 476 and 481 of CHIKV nsP2) have been shown to be important for the protease activity of VEEV nsP223. Known 3D structure coupled with the functional importance of nsP2 have made this protein an attractive target for the development of inhibitors of alphavirus infection232425262728.…”

mentioning

confidence: 99%

Chikungunya virus infectivity, RNA replication and non-structural polyprotein processing depend on the nsP2 protease’s active site cysteine residue

Rausalu

Utt

Quirin

et al. 2016

Sci Rep

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Chikungunya virus (CHIKV), genus Alphavirus, family Togaviridae, has a positive-stand RNA genome approximately 12 kb in length. In infected cells, the genome is translated into non-structural polyprotein P1234, an inactive precursor of the viral replicase, which is activated by cleavages carried out by the non-structural protease, nsP2. We have characterized CHIKV nsP2 using both cell-free and cell-based assays. First, we show that Cys478 residue in the active site of CHIKV nsP2 is indispensable for P1234 processing. Second, the substrate requirements of CHIKV nsP2 are quite similar to those of nsP2 of related Semliki Forest virus (SFV). Third, substitution of Ser482 residue, recently reported to contribute to the protease activity of nsP2, with Ala has almost no negative effect on the protease activity of CHIKV nsP2. Fourth, Cys478 to Ala as well as Trp479 to Ala mutations in nsP2 completely abolished RNA replication in CHIKV and SFV trans-replication systems. In contrast, trans-replicases with Ser482 to Ala mutation were similar to wild type counterparts. Fifth, Cys478 to Ala as well as Trp479 to Ala mutations in nsP2 abolished the rescue of infectious virus from CHIKV RNA transcripts while Ser482 to Ala mutation had no effect. Thus, CHIKV nsP2 is a cysteine protease.Chikungunya virus (CHIKV) belongs to genus Alphavirus (family Togaviridae). It is transmitted by Aedes mosquitoes and has caused several massive outbreaks since 2004 1 . CHIKV has a positive-strand RNA genome approximately 12 kb in length. A large 5′ open reading frame (ORF), which covers 2/3 of the viral genome, is translated directly from the viral genomic RNA and encodes for a non-structural (ns) polyprotein designated as P1234. The second ORF encodes for the precursors of viral structural proteins and is translated from a specific subgenomic RNA synthesized in virus-infected cells 2 .All virus-specific enzymatic activities, required for viral RNA synthesis, are present in P1234 and its cleavage products 3 . Allthough uncleaved P1234 possesses several enzymatic activities 4 , it is incapable of performing viral RNA replication at detectable levels 5 . To become active, P1234 must first be processed into the early replicase (P123 polyprotein + nsP4). This complex can, in principle, perform all the essential steps of viral RNA synthesis 6 . However, during alphavirus infection the early replicase is converted into the mature (nsP1 + nsP2 + nsP3 + nsP4) form 7 . All these cleavages are performed by a protease located at the C-terminus of nsP2 [8][9][10] and the processing of P1234 is regulated at multiple levels [11][12][13][14] .The protease part of nsP2 can be easily purified as an active recombinant protein 10,15 . In addition, the protease activity of nsP2 can be studied using in vitro translation and cell culture models 9,16 . Early studies showed that alphavirus nsP2 is similar to papaine-like proteases. The catalytic dyad of Sindbis virus (SINV) nsP2 is represented by Cys481 and His558 residues 8,17,18 ; these correspond to Cys478 and His54...

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“…In another study, carried out by Jadav and coworkers, series of arylalkylidene derivatives of 1,3-thiazolidin-4-one were synthesized and tested in a similar cell culture assay. In this study, the most active compound had an IC 50 below 1 μM and molecular docking simulation suggested protease inhibition as a possible mode of action (Jadav et al 2015). Recently, for the first time, a new panel of predicted nsP2 inhibitors was shown to inhibit both the protease activity of nsP2 as well as CHIKV replication in cell culture (Das et al 2016).…”

Section: Interaction With Other Viral and Host Proteinsmentioning

confidence: 71%

Functions of Chikungunya Virus Nonstructural Proteins

Ahola

Merits

2016

Chikungunya Virus

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IntroductionThe nonstructural proteins (nsPs) of chikungunya virus (CHIKV) and other alphaviruses are encoded at the 5′ region of the positive-strand viral RNA genome, and thus translated directly after the entry of the RNA into the cytoplasm, to enable the immediate start of the RNA replication process. Many of the replicative functions remain poorly studied for CHIKV nsPs, but have been earlier characterized for proteins from other alphaviruses, primarily Semliki Forest virus (SFV) and Sindbis virus (SINV; Kaariainen and Ahola 2002). It is expected that the basic biochemical functions are conserved in CHIKV proteins, the amino acid (aa) sequence of which are on average 71 % identical with the more closely related SFV nsPs. Therefore we review data from CHIKV whenever available, but also draw heavily on other alphaviruses, and point out the uncertainties regarding the functions of CHIKV proteins.Secondly, the nsPs have many functions in host-virus interactions, including the evasion of antiviral responses. Clearly, these functions are more virus-(and/or celltype) specific in nature, so care needs to be taken in making inferences regarding CHIKV. For instance, it has been shown that hnRNP K, a cellular protein identified as a pro-viral (essential) factor for CHIKV replication (Bourai et al. 2012) acts as a negative effector of replication for SFV (Varjak et al. 2013). A primary division within the mammalian/avian alphaviruses lies between the Old World viruses (e.g., CHIKV, SFV, and SINV) and the New World viruses (e.g., Venezuelan equine encephalitis virus, VEEV), and these two groups display quite different modes of T. Ahola

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Thiazolidone derivatives as inhibitors of chikungunya virus

Cited by 52 publications

References 34 publications

Design and Validation of Novel Chikungunya Virus Protease Inhibitors

Design and Validation of Novel Chikungunya Virus Protease Inhibitors

Chikungunya virus infectivity, RNA replication and non-structural polyprotein processing depend on the nsP2 protease’s active site cysteine residue

Functions of Chikungunya Virus Nonstructural Proteins

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