Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication

Ibba, Roberta; Riu, Federico; Delogu, Ilenia; Lupinu, Ilenia; Carboni, Gavino; Loddo, Roberta; Piras, Sandra; Carta, Antonio

doi:10.3390/v14061300

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…It may be that the PI animals produced continuously expel viruses to the external environment, leading to the expansion of infection. Some literature points out that there is no antiviral drug to prevent the spread of BVDV in the farm at present, and the spread of the virus can only be prevented by isolating PI animals or vaccinating ( 177 ). Therefore, BVDV detection should be done well in the breeding season to reduce the production of PI animals and control the spread of BVDV from the source.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of bovine viral diarrhea virus in cattle between 2010 and 2021: A global systematic review and meta-analysis

Wang

Liu

et al. 2023

Front. Vet. Sci.

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BackgroundBovine viral diarrhea is one of the diseases that cause huge economic losses in animal husbandry. Many countries or regions have successively introduced eradication plans, but BVDV still has a high prevalence in the world. This meta-analysis aims to investigate the prevalence and risk factors of BVDV in the world in recent 10 years, and is expected to provide some reference and theoretical basis for BVDV control plans in different regions.MethodRelevant articles published from 2010 to 2021 were mainly retrieved from NCBI, ScienceDirect, Chongqing VIP, Chinese web of knowledge (CNKI), web of science and Wanfang databases.Results128 data were used to analyze the prevalence of BVDV from 2010 to 2021. BVDV antigen prevalence rate is 15.74% (95% CI: 11.35–20.68), antibody prevalence rate is 42.77% (95% CI: 37.01–48.63). In the two databases of antigen and antibody, regions, sampling time, samples, detection methods, species, health status, age, sex, breeding mode, and seasonal subgroups were discussed and analyzed, respectively. In the antigen database, the prevalence of dairy cows in the breed subgroup, ELISA in the detection method subgroup, ear tissue in the sample subgroup, and extensive breeding in the breeding mode were the lowest, with significant differences. In the antibody database, the prevalence rate of dairy cows in the breed subgroup and intensive farming was the highest, with a significant difference. The subgroups in the remaining two databases were not significantly different.ConclusionThis meta-analysis determined the prevalence of BVDV in global cattle herds from 2010 to 2021. The prevalence of BVDV varies from region to region, and the situation is still not optimistic. In daily feeding, we should pay attention to the rigorous and comprehensive management to minimize the spread of virus. The government should enforce BVDV prevention and control, implement control or eradication policies according to local conditions, and adjust the policies in time.

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Section: Discussionmentioning

confidence: 99%

Prevalence of bovine viral diarrhea virus in cattle between 2010 and 2021: A global systematic review and meta-analysis

Wang

Liu

et al. 2023

Front. Vet. Sci.

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“…However, the antiviral activities of these old drugs are not very satisfactory. Benzimidazole derivatives display a variety of biological activities in many diseases through various mechanisms, such as antiviral [ 28 , 29 ], antimicrobial [ 30 , 31 ], antiproliferative [ 32 , 33 ], and anticancer activities [ 34 , 35 ]. Benzimidazole derivatives are special lead compounds for antiviral drugs, attracting interest from many chemists [ 18 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Chen

Wang

et al. 2023

Molecules

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The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d−Z, 7h−Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10−7 M) in SPR study. The compound 7h−Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure–activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV.

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“…Albeit vaccines are effective against BVDV, and cover BVDV infections, additional therapy is required to eradicate BVDV infections [ 7 ]. With this aim, a promising option is the use of non-nucleoside inhibitors (NNIs), that specifically target the active form of BVDV RdRp, which is differentiated by the positioning of linker and hood ( Figure 1 A,B) [ 4 , 8 ]. Following this route, some selective anti-BVDV inhibitors have been discovered [ 2 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…With this aim, a promising option is the use of non-nucleoside inhibitors (NNIs), that specifically target the active form of BVDV RdRp, which is differentiated by the positioning of linker and hood ( Figure 1 A,B) [ 4 , 8 ]. Following this route, some selective anti-BVDV inhibitors have been discovered [ 2 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. 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.…”

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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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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Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication

Cited by 5 publications

References 38 publications

Prevalence of bovine viral diarrhea virus in cattle between 2010 and 2021: A global systematic review and meta-analysis

Prevalence of bovine viral diarrhea virus in cattle between 2010 and 2021: A global systematic review and meta-analysis

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

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

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