Characterization dengue virus resistance brequinar cell culture

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J Virol , 85 21 , 24 Aug J Virol , 85 13 , 20 Apr Antimicrob Agents Chemother , 50 4 , 01 Apr Virology , 1 , 05 Dec Antiviral Res , 2 , 27 Sep Cited by: articles PMID: Antiviral Res , 80 2 , 30 Jul Cited by: 99 articles PMID: Cited by: 4 articles PMID: Cited by: 7 articles PMID: Contact us. Europe PMC requires Javascript to function effectively. Recent Activity. Search life-sciences literature Over 39 million articles, preprints and more Search Advanced search.

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Search articles by 'Min Qing'. Qing M 1 ,. Zou G ,. Wang QY ,. Xu HY ,. Hongping Dong Search articles by 'Hongping Dong'.

Dong H ,. Zhiming Yuan Search articles by 'Zhiming Yuan'. Yuan Z ,. Shi PY. Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Brequinar is an inhibitor of dihydroorotate dehydrogenase, an enzyme that is required for de novo pyrimidine biosynthesis.

Free full text. Antimicrob Agents Chemother. Published online Jul 6. PMID: Author information Article notes Copyright and License information Disclaimer. Phone for Qing-Yin Wang: 65 Fax: 65 E-mail: moc. Phone for Pei-Yong Shi: 65 This article has been cited by other articles in PMC.

Go to:. Viruses, compound, antibodies, and cell culture media. CFI assay. Viral titer reduction assay. Time-of-addition analysis. Transient replicon assay. Plasmid construction. In vitro transcription and RNA transfection. VLP assay. Viral growth kinetics and plaque assay. Antiviral activity of BQR. Open in a separate window. Envelope or NS5 mutation alone is sufficient to confer resistance. Ackermann, M. Batt, D. Inhibitors of dihydroorotate dehydrogenase. Expert Opin.

Patents 9 : Benarroch, D. Egloff, L. Mulard, C. Guerreiro, J. Romette, and B. Crotty, S. Maag, J. Arnold, W. Zhong, J. Lau, Z.

Hong, R. Andino, and C. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Erratum, 7: , Egloff, M.

Benarroch, B. Selisko, J. EMBO J. Falgout, B. Miller, and C. Foster, G. Hepatitis C virus therapy to date. Gubler, D. Kuno, and L. Flaviviruses, p. Knipe and P. Howley ed. Guo, J. Hayashi, and C. West Nile virus inhibits the signal transduction pathway of alpha interferon. Hwee, T. Stanford, and M. January Dihydroorotate dehydrogenase inhibitors for the treatment of viral-mediated diseases. Jordan, I. Briese, N. Fischer, J. Lau, and W. Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells.

Khromykh, A. Varnavski, P. Sedlak, and E. Kummerer, B. Mutations in the yellow fever virus nonstructural protein NS2A selectively block production of infectious particles.

Leyssen, P. Balzarini, E. De Clercq, and J. The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase.

Lindenbach, B. Thiel, and C. Flaviviridae: the virus and their replication, p. Liu, S. Neidhardt, T. Grossman, T. Ocain, and J. If patients are treated with brequinar, its ability to augment IFN-induced ISRE activation should enhance the overall antiviral status of patients.

In addition, the activation level of IRES was modest even at high concentrations of ribavirin. There is an urgent unmet medical need to develop a safe and effective antiviral for DENV infection. Although no single compound has been approved for clinical use, the possibility of repurposing clinically tried or approved drugs for DENV is a tractable option.

To this end, balapiravir, a cytidine nucleoside analog that was stopped for HCV clinical development, was tested in dengue patients; unfortunately, the compound did not show any efficacy in the dengue clinical trial Similarly, celgosivir, a host alpha-glucosidase inhibitor initially developed for HCV , also failed to show a significant difference compared to placebo An alternative approach for repurposing clinically approved drugs for DENV is to search for a combination therapy.

Such an approach has two conceptual advantages. First, synergy between two drugs would allow one to achieve efficacy at lower doses, leading to an increased therapeutic window for potentially toxic compounds Theoretical and experimental studies have shown that drugs that exhibit synergy for a specific effect are usually not synergistic for side effects 32 , Indeed, toxicity experiments suggested that the observed antiviral synergy of the ribavirin-plus-INX combination was not due to cytotoxicity Fig.

However, due to the unpredictable nature of toxicity associated with nucleoside analogs, caution should be taken in extrapolating in vitro toxicity results. Second, combination treatment would minimize the chance of resistance.

In the absence of effective monotherapy for DENV, a combination of two moderately effective drugs may be needed. This is evident in the treatment of HIV, where only a combination of drugs effectively reduces viremia to an undetectable level. These considerations make synergistic drug pairs ideal candidates for treatment of infectious pathogens. The current study used DENV-2 as a model to achieve proof of concept.

Future studies are needed to expand the current observation in cell culture to an appropriate in vivo study. Read article at publisher's site DOI : Mol Biol , 55 6 , 17 Dec Viruses , 13 12 , 14 Dec Int J Oral Sci , 13 1 :3, 29 Jan Antimicrob Agents Chemother , 64 12 , 17 Nov To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

J Virol , 85 13 , 20 Apr Antiviral Res , , 01 Aug Cited by: 25 articles PMID: Viruses , 10 6 , 09 Jun Antimicrob Agents Chemother , 54 8 , 01 Jun Antiviral Res , , 19 Jan Cited by: 28 articles PMID: Antiviral Res , 2 , 27 Sep Cited by: articles PMID: Contact us. Europe PMC requires Javascript to function effectively.

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Search articles by 'Kim Long Yeo'. Yeo KL 1 ,. Search articles by 'Yen-Liang Chen'. Chen YL 1 ,. Search articles by 'Hao Ying Xu'. Search articles by 'Hongping Dong'. Dong H 1 ,.

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Affiliations 6 authors 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Free full text. Antimicrob Agents Chemother. Published online Mar Prepublished online Jan PMID: Author information Article notes Copyright and License information Disclaimer.

Corresponding author. Address correspondence to Pei-Yong Shi, moc. Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors.

Antimicrob Agents Chemother — All Rights Reserved. This article has been cited by other articles in PMC. Go to:. Cells and culture media. DENV replicon antiviral assay. Cell viability assay. Statistical analysis.

Antiviral activities of individual compounds. Open in a separate window. FIG 1. Antiviral activities of combination treatments. FIG 2. Google Scholar. Phillips, M. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Drug Targets 10 , — A long-duration dihydroorotate dehydrogenase inhibitor DSM for prevention and treatment of malaria. Wachsman, M. Antiviral activity of inhibitors of pyrimidine de-novo biosynthesis. Antiviral Chem. Davis, I.

Leflunomide prevents alveolar fluid clearance inhibition by respiratory syncytial virus. Care Med. Qing, M. Characterization of dengue virus resistance to brequinar in cell culture. Agents Chemother. Zhang, L. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export.

Cell Biol. Chacko, B. Leflunomide for cytomegalovirus: bench to bedside. He, T. Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis. Oncogene 33 , — Vyas, V. Design, synthesis and pharmacological evaluation of novel substituted quinolinecarboxamide derivatives as human dihydroorotate dehydrogenase hDHODH inhibitors and anticancer agents.

Copeland, R. Recombinant human dihydroorotate dehydrogenase: expression, purification, and characterization of a catalytically functional truncated enzyme. Knecht, W. Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid.

Zameitat, E. Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans. FEBS J. Lolli, M. New inhibitors of dihydroorotate dehydrogenase DHODH based on the 4-hydroxy-1, 2, 5-oxadiazolyl hydroxyfurazanyl scaffold. Yin, S. Sensitive and selective determination of orotic acid in biological specimens using a novel fluorogenic reaction. Yie, S. Detection of survivin-expressing circulating cancer cells CCCs in peripheral blood of patients with castric and colorectal cancer reveals high risks of relapse.

Kania, J. Expression of survivin and caspase-3 in gastric cancer. Baumgartner, R. According to the propagation path map, the sample virus entered Guangzhou during — According to the propagation path, the sample virus was imported into Guangzhou during — It is difficult to infer a highly accurate propagation path as no more sequences are available from the GenBank database. The propagation path map of all sample viruses is included in Fig 4.

The MCC trees are shown in Figs 5 — 9. The propagation path map is drawn based on the paleogeography analysis. The red curves indicated that the clusters of sample sequences were belonged to DENV-1, while the blue curves belonged to DENV-2, which indicated the propagation path. The time beside the curves indicates the time range in which the virus strain is introduced, and the red flag indicates different locations. A A root-to-tip analysis was performed in TempEst v1. B Sequences from different geographic regions are represented by different colors.

The location on the branch is the most recent ancestor position, and the value is the posterior probability. The purple branch indicates that Fujian Province is the most recent ancestor of the sequences; the green branch corresponds to Malaysia; the blue branch corresponds to Taiwan Province; and the red branch corresponds to Guangzhou.

The dotted line box represents the sample sequence obtained in this experiment. The blue branch indicates that Singapore is the most recent ancestor of the sequences; and the red branch corresponds to Guangzhou.

The green branch indicates that Singapore is the most recent ancestor of the sequences; the blue branch corresponds to Taiwan Province; and the red branch corresponds to Guangzhou. The purple branch indicates that Indonesia is the most recent ancestor of the sequences; the blue branch corresponds to Malaysia; the orange branch corresponds to Zhongshan City; the green branch corresponds to East Timor; and the red branch corresponds to Guangzhou.

The purple branch indicates that Malaysia is the most recent ancestor of the sequences; the green branch corresponds to India; the blue branch corresponds to Taiwan province; and the red branch corresponds to Guangzhou.

The five sample clusters were compared with the genetic distances of the same genotype in clusters in — It can be seen from the table that the sequence of the DENV-2 two-cluster sample collected in this study differs greatly from the sequence of the same genotype.

The sequence differences between other sample clusters and the same genotype are small. The data is presented in Table 4. In the present study, blood samples were drawn from DENV-infected patients who were diagnosed with dengue fever by hospitals in Guangzhou during , and an analysis was performed on the DENV strains isolated from these blood samples.

The ancestral reconstruction analysis showed that the sample sequences largely originated from Indonesia, Malaysia, Singapore, and Taiwan. This suggests that the dengue virus that we are popular in Guangzhou is still based on input. As the capital city of Guangdong Province and the trade center in Southeast China, Guangzhou is exposed to a relatively high risk of the disease, as DENV may enter the city along with imported goods and migrant workers.

Therefore, entry-exit inspection and quarantine should be implemented effectively for dengue prevention and control. For instance, suspected and confirmed cases of DENV infection should be isolated and treated properly to reduce the risk of imported dengue fever. In addition, health education also plays an important role in dengue prevention and control.

To reduce the risk of DENV infection, public health authorities should provide the necessary materials for tourists to gain a better understanding of dengue prevention and remind them not to visit an endemic area during epidemic seasons. Interestingly, the results from the traceability analysis showed that the most recent common ancestor of the sequences of cluster II emerged from Guangzhou, and Cluster II and the Guangzhou isolate are in the same branch without any other foreign sequences.

Moreover, they shared a common ancestral lineage to the Malaysian isolate, the Singaporean isolate, and the Zhongshan isolate in other branches. Phylogeographically, there are two possible propagation paths.

First, the virus originated in Singapore and became an epidemic in the country before ; during the next year, it was imported into Zhongshan, and then in , the disease flowed into Guangzhou from other cities in Guangdong Province; the Guangzhou isolates came from the virus imported into the city during as a result of local transmission.

Second, the virus emerged from Singapore and was not introduced into Zhongshan until ; during and , the virus was continuously imported into Guangzhou from Singapore or other countries and regions; the sample sequences were not clustered into a branch with the isolates from other countries because no related sequences were available in GenBank or the database had no sufficient patient isolates.

Regarding the sources of spread or propagation, some DENV strains were imported from endemic countries and regions and caused dengue fever without further propagation in China; some evolved from imported strains and led to local epidemics during the year; others were localized strains after vertical transmission. Although no substantial evidence was found in this study to prove vertical transmission of DENV in Guangzhou, previous phylogenetic analyses indicated possible local transmission of dengue fever in the city.

Since Aedes albopictus is the main medium for DENV transmission, the localization of DENV largely depends on the formation of localized and virus-carrying eggs and the survival of DENV in the eggs and offspring mosquitoes through winter[ 34 ]. A previous study demonstrated that DENV can survive in eggs and spread to offspring mosquitoes.

Transovarial transmission of DENV is strongly temperature-related as it determines whether the eggs and young offspring can wait out the winter season. As an example, Yunnan Province has reported the localization of DENV as it has a subtropical monsoon climate and provides a natural habitat for Aedes albopictus.

Similar to Yunnan Province, Guangzhou has hot, humid summers and mild, dry winters, which create a favorable environment for the breeding of Aedes mosquitoes.

Moreover, as the greenhouse effect continues to warm the planet slowly, overwintering becomes easier for mosquitoes. Peri-urban areas in Guangzhou have plenty of dirty gullies, open spaces, and rented houses that require effective management to improve the living environment. Additionally, local residents who like indoor and outdoor planting, fish farming, and water harvesting also provide places for mosquito breeding.

To reduce mosquito breeding sites, effective urban sanitation management should be implemented. For example, stagnant water should be cleared in a timely manner to ensure the smooth operation and maintenance of the city's drainage system; in crowded places, mosquito prevention and control measures should be taken for the public good. Personal hygiene also plays a critical role in dengue prevention. Residents should avoid keeping fish and aquatic plants and regularly clean up stagnant water in their houses.

An individual with a fever or other dengue fever-like symptoms should promptly seek medical attention. Hospitals should strive to improve the diagnostic accuracy and efficiency of dengue fever. Suspected DENV-infected patients should be isolated to prevent further transmission. We should pay closer attention to localized DENV in Guangzhou and strictly implement relevant dengue prevention and control measures. Although the results of this study implied that vertical transmission of DENV might exist in Guangzhou, there is no solid evidence supporting the inference as no adequate sequences are available for analysis.

The coverage of the sequence has a great impact on the study. Patients with dengue sometimes have negative infections. The patient is not aware that the infection with dengue virus has led to a decrease in the reported sequence, and a small number of viruses have not been sequenced and uploaded to the database. These can all lead to the wrong propagation path.

Therefore, local centers for disease control and prevention should work closely with disease control and prevention departments of Southeast Asian countries to observe how DENV is prevalent in these countries, thereby identifying sources of propagation for DENV in China and exploring the epidemiological characteristics of dengue fever to provide a basis for dengue prevention strategies.

As the Belt and Road Initiative moves forward, Asian, European and African countries expect to increase transport connections for international trade, strengthen people-to-people exchanges and remove barriers to investment and trade.