Mechanism of drug resistance of BVDV induced by F224S mutation in RdRp: A case study of VP32947

He, Dengfa; Li, Xuedong; Wang, Songsong; Wang, Chengzhao; Liu, Xingang; Zhang, Yang; Chen, Yan; Yu, Sijiu

doi:10.1016/j.compbiolchem.2022.107715

Cited by 2 publications

(3 citation statements)

References 46 publications

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“…Interestingly, the identified most likely binding sites of 2h and 5m coincide well with already reported resistant mutants, indicating that quinoline series possibly occupy the template entrance site, as we have reported this site earlier, for the benzimidazole class of compounds. The reported mutation residues, such as F224S/Y [ 4 , 5 , 17 ], E291G [ 34 ], I261M [ 5 ], N264D [ 14 ], and A392E [ 16 ] ( Table S8 ), lead two points to be underscored here: (i) All the reported resistant mutants for different classes of compounds are localized in the vicinity of each other, making the zone a hot-spot; (ii) these mutations are common, even for different classes of drugs—F224S/Y is the resistant mutant for indole, imidazopyridine and pyrimidine-amine ( Table S8 )—indicating the criticality of these residues. We assume that, by mutating these residues, the RdRp is able to resume its function (possibly with different rates with respect to WT).…”

Section: Resultsmentioning

confidence: 99%

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Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

et al. 2023

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The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication; therefore, it is one of the primary targets for countermeasures against infectious diseases. The reported NNIs, belonging to the classes of quinolines (2h: imidazo[4,5-g]quinolines and 5m: pyrido[2,3-g] quinoxalines), displayed activity in cell-based and enzyme-based assays. Nevertheless, the RdRp binding site and microscopic mechanistic action are still elusive, and can be explored at a molecular level. Here, we employed a varied computational arsenal, including conventional and accelerated methods, to identify quinoline compounds’ most likely binding sites. Our study revealed A392 and I261 as the mutations that can render RdRp resistant against quinoline compounds. In particular, for ligand 2h, mutation of A392E is the most probable mutation. The loop L1 and linker of the fingertip is recognized as a pivotal structural determinant for the stability and escape of quinoline compounds. Overall, this work demonstrates that the quinoline inhibitors bind at the template entrance channel, which is governed by conformational dynamics of interactions with loops and linker residues, and reveals structural and mechanistic insights into inhibition phenomena, for the discovery of improved antivirals.

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Section: Resultsmentioning

confidence: 99%

“…However, the molecular recognition of BVDV RdRp with allosteric NNIs has not been extensively studied, as no co-crystallized NNI-RdRp has been published to our knowledge. However, several mutagenic information-based computational docking studies have been reported to date [ 4 , 5 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

et al. 2023

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“…These findings imply that many farms have infected animals (Evans et al 2019). In the present scenario, the most effective approach to controlling BVDV transmission involves combining vaccination with the detection and elimination of persistently infected cattle from healthy groups (He et al 2022). Due to the continuous mutation of BVDV strains, existing BVDV vaccines do not offer complete protection against all BVDV1 and BVDV2 strains (Wang et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Development and Application of a Rapid Test for Detection of Bovine Viral Diarrhea Virus-specific Antibodies

2024

Int J Vet Sci

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Bovine viral diarrhea virus (BVDV) is an economically consequential animal pathogen that engenders substantial financial losses in the realm of cattle farming, and it maintains a prevalent presence on a global scale. Presently, the prevailing modality employed for its detection is enzyme-linked immunosorbent assay (ELISA), which necessitates the use of sophisticated instrumentation, protracts the duration of analysis, and is primarily suited for laboratory-based diagnostics. Regrettably, ELISAs do not lend themselves to convenient on-site detection within cattle farms. To surmount this predicament, colloidal gold particles were synthesized using tri-sodium citrate reduction, and subsequently harnessed to label the E2 protein (E2-Au). By amalgamating the gold standard binding release pad with colloidal E2-Au, we have devised a comprehensive assay system. The nitrocellulose membrane serves as the platform, whereby the detection line is adorned with E2-Au, while the quality control line is coated with proprietary polyclonal rabbit antibodies specific to E2. The method yields results within a span of 10-15 minutes, exhibiting an impressive total compliance rate of 93.36% (239/256) when compared to the commercial kit. The E2 test strip demonstrates specific reactivity with the anti-BVDV antibody, while avoiding any cross-reactivity with antibodies targeting Brucella, bovine foot and mouth disease, Mycobacterium bovis, bovine para-tuberculosis, bovine pasteurellosis, and bovine infectious rhinotracheitis. Consequently, the E2 strips offer heightened specificity, cost-effectiveness, and ease of operation, rendering them more convenient and expedient in comparison to ELISA kits. Utilizing the E2 strips, a comprehensive assessment encompassing 36 cattle farms and 2035 cattle in the vicinity of Xinjiang, China, was conducted. The positive rate within the group reached an impressive 91.67%, with individual positive rates standing at 54.05%.

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Mechanism of drug resistance of BVDV induced by F224S mutation in RdRp: A case study of VP32947

Cited by 2 publications

References 46 publications

Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

Development and Application of a Rapid Test for Detection of Bovine Viral Diarrhea Virus-specific Antibodies

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