Limits...
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.

Show MeSH

Related in: MedlinePlus

Proteins in the tree shrew identified as potential drug targets.(A) 586 kinase proteins with 2,324 gene isoforms were predicted as drug targets from 2,614 coding transcripts. (B) 1,074 GPCR proteins were predicted from 1,439 coding transcripts divided into four classes. (C) 116 ion channel proteins were predicted from 337 coding transcripts. (D) 709 immune genes were predicted from 1,986 coding transcripts. (E) 151 neuropeptides were predicted from 412 coding transcripts. (F) 1,011 proteinases and inhibitors were predicted from 2,842 coding transcripts. (G) 44 nuclear receptors were predicted from 126 coding transcripts.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126716&req=5

pone-0104191-g002: Proteins in the tree shrew identified as potential drug targets.(A) 586 kinase proteins with 2,324 gene isoforms were predicted as drug targets from 2,614 coding transcripts. (B) 1,074 GPCR proteins were predicted from 1,439 coding transcripts divided into four classes. (C) 116 ion channel proteins were predicted from 337 coding transcripts. (D) 709 immune genes were predicted from 1,986 coding transcripts. (E) 151 neuropeptides were predicted from 412 coding transcripts. (F) 1,011 proteinases and inhibitors were predicted from 2,842 coding transcripts. (G) 44 nuclear receptors were predicted from 126 coding transcripts.

Mentions: Based on Pfam domain annotation, 2,614 coding transcripts with kinase domains were extracted from the tree shrew transcriptome gene sets (Figure 2A; Table S1 in File S1). OrthoMCL was used to cluster these domains into 129 groups based on a reference dataset (KINBASE) combined with phylogenetic analysis. Tree shrew GPCRs were identified using HMMTOP and GPCRDB searching, resulting in 1,439 tree shrew GPCRs that coded transcripts classified and annotated into four families: the rhodopsin family (n  =  1,244), the secretin receptor family (n  =  115), the metabotropic glutamate receptor family (n  =  47) and others (n  =  33) (Figure 2B; Table S2 in File S1). Similar to results from other species, 47.6% of the GPCR transcripts were annotated as olfactory receptors. To search for ion channel proteins, vertebrate ligand-gated ion channel (LGIC) subunits were used in BLAST queries against the tree shrew transcriptome. After ranking the resulting hits based on E-values (1e-10 cutoff) and removing redundant sequences, 337 ion channel-coding transcripts were identified (Figure 2C; Table S3 in File S1). To identify genes of the immune system, we performed a database query of the tree shrew transcriptome against the Immunome database. Using a cutoff E-value of 1e-10, 1,986 immune-coding protein transcripts were identified in the transcriptome (Figure 2D; Table S4 in File S1). Scanning for neuropeptides was performed using a stringent search against NeuroPedia followed by manual comparison to similar species. Combined with the results of the database query search, we recovered 412 neuropeptide coding transcripts from the tree shrew transcriptome (Figure 2E; Table S5 in File S1). A total of 2,842 coding transcripts of putative peptidases and peptidase inhibitors were detected using the MEROPS database server (Figure 2F; Table S6 in File S1). Similar to numbers reported for other primate species, 120 protease gene families were identified in the tree shrew. Nuclear receptors were detected by KEGG annotation, resulting in the identification of 126 putative nuclear receptor-coding transcripts in the tree shrew (Figure 2G; Table S7 in File S1).


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)

Proteins in the tree shrew identified as potential drug targets.(A) 586 kinase proteins with 2,324 gene isoforms were predicted as drug targets from 2,614 coding transcripts. (B) 1,074 GPCR proteins were predicted from 1,439 coding transcripts divided into four classes. (C) 116 ion channel proteins were predicted from 337 coding transcripts. (D) 709 immune genes were predicted from 1,986 coding transcripts. (E) 151 neuropeptides were predicted from 412 coding transcripts. (F) 1,011 proteinases and inhibitors were predicted from 2,842 coding transcripts. (G) 44 nuclear receptors were predicted from 126 coding transcripts.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104191-g002: Proteins in the tree shrew identified as potential drug targets.(A) 586 kinase proteins with 2,324 gene isoforms were predicted as drug targets from 2,614 coding transcripts. (B) 1,074 GPCR proteins were predicted from 1,439 coding transcripts divided into four classes. (C) 116 ion channel proteins were predicted from 337 coding transcripts. (D) 709 immune genes were predicted from 1,986 coding transcripts. (E) 151 neuropeptides were predicted from 412 coding transcripts. (F) 1,011 proteinases and inhibitors were predicted from 2,842 coding transcripts. (G) 44 nuclear receptors were predicted from 126 coding transcripts.
Mentions: Based on Pfam domain annotation, 2,614 coding transcripts with kinase domains were extracted from the tree shrew transcriptome gene sets (Figure 2A; Table S1 in File S1). OrthoMCL was used to cluster these domains into 129 groups based on a reference dataset (KINBASE) combined with phylogenetic analysis. Tree shrew GPCRs were identified using HMMTOP and GPCRDB searching, resulting in 1,439 tree shrew GPCRs that coded transcripts classified and annotated into four families: the rhodopsin family (n  =  1,244), the secretin receptor family (n  =  115), the metabotropic glutamate receptor family (n  =  47) and others (n  =  33) (Figure 2B; Table S2 in File S1). Similar to results from other species, 47.6% of the GPCR transcripts were annotated as olfactory receptors. To search for ion channel proteins, vertebrate ligand-gated ion channel (LGIC) subunits were used in BLAST queries against the tree shrew transcriptome. After ranking the resulting hits based on E-values (1e-10 cutoff) and removing redundant sequences, 337 ion channel-coding transcripts were identified (Figure 2C; Table S3 in File S1). To identify genes of the immune system, we performed a database query of the tree shrew transcriptome against the Immunome database. Using a cutoff E-value of 1e-10, 1,986 immune-coding protein transcripts were identified in the transcriptome (Figure 2D; Table S4 in File S1). Scanning for neuropeptides was performed using a stringent search against NeuroPedia followed by manual comparison to similar species. Combined with the results of the database query search, we recovered 412 neuropeptide coding transcripts from the tree shrew transcriptome (Figure 2E; Table S5 in File S1). A total of 2,842 coding transcripts of putative peptidases and peptidase inhibitors were detected using the MEROPS database server (Figure 2F; Table S6 in File S1). Similar to numbers reported for other primate species, 120 protease gene families were identified in the tree shrew. Nuclear receptors were detected by KEGG annotation, resulting in the identification of 126 putative nuclear receptor-coding transcripts in the tree shrew (Figure 2G; Table S7 in File S1).

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