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Prioritising Drug Targets for Antimalarial Drugs

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Shi Ruifei

Introduction

Plasmodium is a single-celled amoeba which can cause malaria. In mosquitoes’ and human liver and blood, they represent in several different shapes and sizes for the sake of escaping from the attack of immune system. There is no symptom when Plasmodium in human liver, they start to thrive after entering the red blood cells then severely result in the break of red blood cells, finally causing the alternating hot and cold symptoms in patients. Indeed, Plasmodium falciparum is a protozoan parasite which lead to almost every malarial death for human being.

Isopentenyl pyrophosphate (IPP) is the only indispensable substance for Plasmodium and Plasmodium rely on it to survive in the blood cells . Under normal circumstances, IPP is synthesized and supplied from a unique organelle which called apicoplast, and this organelle only exists in Plasmodium. Among the various synthetic substances from apicoplast, IPP is the only necessary substance in the stage of blood for parasite. Since the way of producing IPP is completely distinctive between human and Plasmodium, so the drug which can destroy the function of synthesizing IPP in parasite will not damage the ability of human cells to synthesize IPP, in the meantime can acheieve the purpose of clearing the parasite.

This assignment will first provide the result after sifting through the genome and promising targets are PF3D7_0623200 , then presenting the bioinformatic analysis and data on the characteristics of this selection of preferred desirable drug targets.

Results and data

1. According to the demand, first step is to identify proteins with desired efficacy, which obtain the physical and chemical characters then become the target protein. Indeed, these proteins will interact with drug-like molecules. Secondly, after selecting Plasmodium falciparum as the organism, I get the data of druggability score which greater than 0. Finally, it comes out with 1551 kinds of target query.

2. I divide next step into two with different filter criteria, the one existing queries with genes that are absent in the whole mammals and the other one are absent only in humans. Then it results in different target query.

# Mammals

1. Druggability score

Gene ID

Gene name

Gene product

Druggability

PF3D7_1443900

PF14_0417

heat shock protein 90, putative( HSP90)

0.3

PF3D7_1406600

PF14_0063

ATP-dependent Clp protease, putative(ClpC)

0.3

PF3D7_0220100

PFB0920w

DnaJ protein, putative

0.1

Figure 1 shows the druggability score of target query which absent in the whole mammals.

As figure 1 shows, the efficacy of these three target query is not ideal enough due to the fact that scores closer to 1 are best.

2.

(1) PF3D7_1443900

cellular component: apicoplast

Figure 2 shows Blood stage transcriptome by RNA-Seq

As figure 2 shows, the Transcript levels reach the peak at the 32 hours during the intraerythrocytic developmental cycle.

Figure 3 shows Transcriptome during intraerythrocytic development

As figure 3 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 4 shows Life cycle expression data

As figure 4 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression reach the peak at the stage of Late Trophs.

One of the molecular function of HSP90 is about ATP-binding. According to the related research, ATP-binding contains biological processes including translocation of various substrates across membranes and non-transport-related processes such as translation of RNA and DNA repair, which need the energy of adenosine triphosphate (ATP). ATP-binding also has strong links with transporting substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs. Hence, the PF3D7_1443900 may contribute to the development of resistance to multiple drugs.

(2) PF3D7_1406600

cellular component: apicoplast

Figure 5 shows Blood stage transcriptome by RNA-Seq

As figure 5 shows, the Transcript levels reach the peak at the 32 hours during the intraerythrocytic developmental cycle.

Figure 6 shows Transcriptome during intraerythrocytic development

As figure 6 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 7 shows Life cycle expression data

As figure 7 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression reach the peak at the stage of Early Schizonts

One of the biological process of ClpC is about protein metabolism. According to the related research, protein metabolism contains different kinds of biochemical processes which are responsible for the synthesis of proteins and amino acids, and the degrade of proteins (including other large molecules) by catabolism. In addition, the PF3D7_1443900 also contribute to the nucleoside-triphosphatase activity and serine-type endopeptidase activity.

(3) PF3D7_0220100

cellular component: membrane

Figure 8 shows Blood stage transcriptome by RNA-Seq

As figure 8 shows, the Transcript levels reach the peak at the first 8 hours during the intraerythrocytic developmental cycle.

Figure 9 shows Transcriptome during intraerythrocytic development

As figure 9 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 10 shows Life cycle expression data

As figure 10 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression reach the peak at the stage of Merozoites.

One of the biological process of DnaJ protein is about protein folding. According to the related research protein folding is the process of a protein how to shape its functional structure and conformation. PF3D7_0220100 has a strong relationship with the protein funtions due to the fact that the correct three-dimensional structure is essential to function, and some parts of functional proteins even remain unfolded. Inactivating of proteins is generally caused by failure to fold into native structure, but to some extent misfolded proteins lead to modified or toxic functionality.

# Homo sapiens

1. Druggability score

Gene ID

Gene name

Gene product

Druggability

PF3D7_0623200

PFF1115w

ferredoxin NADP reductase (FNR)

0.7

PF3D7_0804400

MAL8P1.140

methionine aminopeptidase 1c, putative (MetAP1c)

0.5

PF3D7_0404700

PFD0230c

dipeptidyl peptidase 3 (DPAP3)

0.3

PF3D7_1344800

MAL13P1.221

 

0.1

Figure 11 shows the druggability score of target query which absent only in the human.

2.

(1) PF3D7_0623200

cellular component: apicoplast and thylakoid membrane

Figure 12 shows Blood stage transcriptome by RNA-Seq

As figure 12 shows, the Transcript levels reach the peak at the 24 hour during the intraerythrocytic developmental cycle.

Figure 13 shows Transcriptome during intraerythrocytic development

As figure 13 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 14 shows Life cycle expression data

As figure 14 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression reach the bottom at the stage of Late Schizonts.

One of the molecular function of FNR is about electron carrier activity. According to the previous experiments in malaria parasite apicoplasts, through researching the biochemical properties of ferredoxin (Fd) and Fd-NADP+ reductase (FNR), which probably help to reduce power to Fd-dependent metabolic pathways. The bone structure of P. falciparum Fd, is similar with resembles those of plants Fds. P. falciparum FNR was available to transfer electrons to P. falciparum Fd selectively. Hence, these evidence indicate that PF3D7_0623200 may contribute to the operating of the apicoplast of human malaria parasites in a NADPH-FNR-Fd cascade.

(2) PF3D7_0804400

cellular component: apicoplast

Figure 15 shows Blood stage transcriptome by RNA-Seq

As figure 15 shows, the Transcript levels reach the peak at the 32 hour during the intraerythrocytic developmental cycle.

Figure 16 shows Transcriptome during intraerythrocytic development

As figure 16 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 17 shows Life cycle expression data

As figure 17 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression stay the same during the whole span.

According to the previous reasearch, PF3D7_0804400 is related to the biological process: cellular process and proteolysis. One of the molecular function is metalloexopeptidase activity, which is defined as" Catalysis of the hydrolysis of a peptide bond not more than three residues from the N- or C-terminus of a polypeptide chain by a mechanism in which water acts as a nucleophile, one or two metal ions hold the water molecule in place, and charged amino acid side chains are ligands for the metal ions."

(3) PF3D7_0404700

cellular component: apicoplast

Figure 18 shows Blood stage transcriptome by RNA-Seq

As figure 18 shows, the Transcript levels reach the peak between 40- 48 hour during the intraerythrocytic developmental cycle.

Figure 19 shows Transcriptome during intraerythrocytic development

As figure 19 shows, P. falciparum transcriptome during intraerythrocytic development. Synchronized parasites were assayed by RNA-seq at 8 time-points during the iRBC cycle.

Figure 20 shows Life cycle expression data

As figure 20 shows, nine different stages during the development of P. falciparum 3D7 were assayed by oligonucleotide microarray analysis. The expression reach the peak at the stage of Late Schizonts.

According to the previous reasearch, PF3D7_0404700 is related to the biological process: protein catabolic process and proteolysis . One of the molecular function is cysteine-type peptidase activity.

Discussion

To sum up, PF3D7_0623200 is the most effective target query, since its druggability score is relatively high. However, it may not harmless to all mammals. Beside, according to the analysis of the data of Life cycle expression and Blood stage transcriptome, PF3D7_0623200 is not the most high expression target query. Nevertheless, its related the biological process and molecular function are really important than the others target query for synthesize the drug to acheieve the purpose of clearing the parasite.

References

Zuegge J,Ralph S,Schmuker M,McFadden GI,Schneider G: Deciphering apicoplast targeting signals--feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins. Gene 2011, 280(1-2):19-26.

Kimata AY,Kurisu G,Kusunoki M,Aoki S,Sato D,Kobayashi T,Kita K,Horii T,Hase T- Cloning and characterization of ferredoxin and ferredoxin-NADP+ reductase from human malaria parasite, J Biochem. 2007, 141(3):421-8.

Florens L,Liu X,Wang Y,Yang S,Schwartz O,Peglar M,Carucci DJ,Yates JR 3rd,Wu Y: Proteomics approach reveals novel proteins on the surface of malaria-infected erythrocytes, Mol Biochem Parasitol.2004, 135(1):1-11.

Hall N,Pain A,Berriman M,Churcher C,Harris B,Harris D,Mungall K,Bowman S: Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13, Nature. 2002, 419(6906):527-31.

Ian AL,Mark W,Kellen LO,Simon AC,Katelynn SB,Asako T,Michael TF,Manuel L: Metabolic QTL Analysis Links Chloroquine Resistance inPlasmodium falciparumto Impaired Hemoglobin Catabolism, PLoS Genet 2014;10(1).


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