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Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

Zhao F, Guo X, Wang Y, Liu J, Lee WH, Zhang Y - PLoS ONE (2014)

Bottom Line: The discovery of new drugs requires the development of improved animal models for drug testing.The Chinese tree shrew is considered to be a realistic candidate model.Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, PR China.

ABSTRACT
The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

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Related in: MedlinePlus

Overview of Chinese tree shrew data assembly for drug target analysis.(A) The pipeline of assembled data for drug target analysis. (B) A Venn diagram illustrating the overlap of transcripts obtained from the ab initio and de novo assembly methods. Most transcripts obtained from the two different assembly methods shared the same complete sequence or coding sequence.
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pone-0104191-g001: Overview of Chinese tree shrew data assembly for drug target analysis.(A) The pipeline of assembled data for drug target analysis. (B) A Venn diagram illustrating the overlap of transcripts obtained from the ab initio and de novo assembly methods. Most transcripts obtained from the two different assembly methods shared the same complete sequence or coding sequence.

Mentions: We developed a pipeline for the global annotation of transcripts from RNA sequencing (RNA-seq) data. Because we focused on drug target proteins or domains, our information retrieval system was biased toward predicted protein-coding transcripts (such as homologs of known genes or those with coding potential). Transcriptome assembly was performed using both ab initio and de novo methods. Using the ab initio assembly programs Tophat and Cufflinks, 173,454 transcripts were obtained from seven different tree shrew tissues (brain, heart, liver, kidney, pancreas, ovary and testis). Transcriptome de novo assembly was performed using the SOAPdenovo-trans program to identify 121,817 transcripts (Figure 1A). To maximize the detection of protein-coding transcripts, we used a less stringent but broadly adopted definition that considers a sequence to be protein-coding if it contains the complete coding DNA sequence (CDS) [13]. As a result, 53.2% of the 173,454 transcripts assembled ab initio from 107,429 loci included regions annotated as CDSs. A total of 50.6% of the 121,817 transcripts assembled de novo were annotated as CDSs and aligned with 100% identity to the transcripts assembled by Cufflinks. A comparison of the transcriptomes generated by the two assembly methods (Figure 1B) revealed that 106,773 transcripts could be assembled using either method, although thousands of novel transcripts were identified separately. Consequently, subsequent analyses were based on protein-coding transcripts obtained via ab initio assembly.


Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

Zhao F, Guo X, Wang Y, Liu J, Lee WH, Zhang Y - PLoS ONE (2014)

Overview of Chinese tree shrew data assembly for drug target analysis.(A) The pipeline of assembled data for drug target analysis. (B) A Venn diagram illustrating the overlap of transcripts obtained from the ab initio and de novo assembly methods. Most transcripts obtained from the two different assembly methods shared the same complete sequence or coding sequence.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126716&req=5

pone-0104191-g001: Overview of Chinese tree shrew data assembly for drug target analysis.(A) The pipeline of assembled data for drug target analysis. (B) A Venn diagram illustrating the overlap of transcripts obtained from the ab initio and de novo assembly methods. Most transcripts obtained from the two different assembly methods shared the same complete sequence or coding sequence.
Mentions: We developed a pipeline for the global annotation of transcripts from RNA sequencing (RNA-seq) data. Because we focused on drug target proteins or domains, our information retrieval system was biased toward predicted protein-coding transcripts (such as homologs of known genes or those with coding potential). Transcriptome assembly was performed using both ab initio and de novo methods. Using the ab initio assembly programs Tophat and Cufflinks, 173,454 transcripts were obtained from seven different tree shrew tissues (brain, heart, liver, kidney, pancreas, ovary and testis). Transcriptome de novo assembly was performed using the SOAPdenovo-trans program to identify 121,817 transcripts (Figure 1A). To maximize the detection of protein-coding transcripts, we used a less stringent but broadly adopted definition that considers a sequence to be protein-coding if it contains the complete coding DNA sequence (CDS) [13]. As a result, 53.2% of the 173,454 transcripts assembled ab initio from 107,429 loci included regions annotated as CDSs. A total of 50.6% of the 121,817 transcripts assembled de novo were annotated as CDSs and aligned with 100% identity to the transcripts assembled by Cufflinks. A comparison of the transcriptomes generated by the two assembly methods (Figure 1B) revealed that 106,773 transcripts could be assembled using either method, although thousands of novel transcripts were identified separately. Consequently, subsequent analyses were based on protein-coding transcripts obtained via ab initio assembly.

Bottom Line: The discovery of new drugs requires the development of improved animal models for drug testing.The Chinese tree shrew is considered to be a realistic candidate model.Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, PR China.

ABSTRACT
The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

Show MeSH
Related in: MedlinePlus