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Zika M-A Potential Viroporin: Mutational Study and Drug Repurposing.

ABSTRACT: Genus Flavivirus contains several important human pathogens. Among these, the Zika virus is an emerging etiological agent that merits concern. One of its structural proteins, prM, plays an essential role in viral maturation and assembly, making it an attractive drug and vaccine development target. Herein, we have characterized ZikV-M as a potential viroporin candidate using three different bacteria-based assays. These assays were subsequently employed to screen a library of repurposed drugs from which ten compounds were identified as ZikV-M blockers. Mutational analyses of conserved amino acids in the transmembrane domain of other flaviviruses, including West Nile and Dengue virus, were performed to study their role in ion channel activity. In conclusion, our data show that ZikV-M is a potential ion channel that can be used as a drug target for high throughput screening and drug repurposing.

SUBMITTER: Tomar PPS

PROVIDER: S-EPMC8944957 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Zika M-A Potential Viroporin: Mutational Study and Drug Repurposing.

Tomar Prabhat Pratap Singh PPS Krugliak Miriam M Singh Anamika A Arkin Isaiah T IT

Biomedicines 20220310 3

Genus Flavivirus contains several important human pathogens. Among these, the Zika virus is an emerging etiological agent that merits concern. One of its structural proteins, prM, plays an essential role in viral maturation and assembly, making it an attractive drug and vaccine development target. Herein, we have characterized ZikV-M as a potential viroporin candidate using three different bacteria-based assays. These assays were subsequently employed to screen a library of repurposed drugs from ...[more]

PMID: 35327443

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Project description:BackgroundThe global pandemics of severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 have caused unprecedented crises for public health. Coronaviruses are constantly evolving, and it is unknown which new coronavirus will emerge and when the next coronavirus will sweep across the world. Knowledge graphs are expected to help discover the pathogenicity and transmission mechanism of viruses.ObjectiveThe aim of this study was to discover potential targets and candidate drugs to repurpose for coronaviruses through a knowledge graph-based approach.MethodsWe propose a computational and evidence-based knowledge discovery approach to identify potential targets and candidate drugs for coronaviruses from biomedical literature and well-known knowledge bases. To organize the semantic triples extracted automatically from biomedical literature, a semantic conversion model was designed. The literature knowledge was associated and integrated with existing drug and gene knowledge through semantic mapping, and the coronavirus knowledge graph (CovKG) was constructed. We adopted both the knowledge graph embedding model and the semantic reasoning mechanism to discover unrecorded mechanisms of drug action as well as potential targets and drug candidates. Furthermore, we have provided evidence-based support with a scoring and backtracking mechanism.ResultsThe constructed CovKG contains 17,369,620 triples, of which 641,195 were extracted from biomedical literature, covering 13,065 concept unique identifiers, 209 semantic types, and 97 semantic relations of the Unified Medical Language System. Through multi-source knowledge integration, 475 drugs and 262 targets were mapped to existing knowledge, and 41 new drug mechanisms of action were found by semantic reasoning, which were not recorded in the existing knowledge base. Among the knowledge graph embedding models, TransR outperformed others (mean reciprocal rank=0.2510, Hits@10=0.3505). A total of 33 potential targets and 18 drug candidates were identified for coronaviruses. Among them, 7 novel drugs (ie, quinine, nelfinavir, ivermectin, asunaprevir, tylophorine, Artemisia annua extract, and resveratrol) and 3 highly ranked targets (ie, angiotensin converting enzyme 2, transmembrane serine protease 2, and M protein) were further discussed.ConclusionsWe showed the effectiveness of a knowledge graph-based approach in potential target discovery and drug repurposing for coronaviruses. Our approach can be extended to other viruses or diseases for biomedical knowledge discovery and relevant applications.

Dataset Information

Zika M-A Potential Viroporin: Mutational Study and Drug Repurposing.

Publications

Zika M-A Potential Viroporin: Mutational Study and Drug Repurposing.

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