Identification of Biomarker and Biological Risk Genes to Drive Drug Repurposing in Malaria Using Transcriptomics Database Potential of Transcriptomic data to drive Drug Repurposing for Malaria
Iranian Journal of Pharmaceutical Sciences,
Vol. 19 No. 3 (2023),
1 July 2023
,
Page 250- 260
https://doi.org/10.22037/ijps.v19i3.43886
Abstract
This study applied the transcriptomic-based bioinformatics analysis to systematically integrate data on risk loci for malaria biology and drug discovery from various databases. It was hypothesized that genomic-driven drug repurposing can be utilized as an alternative approach for malaria drug repurposing. Herein, transcriptomic profiles were extracted and retrieved from the NCBI-GEO website by using the keywords "malaria" and "Homo sapiens". In sum, the data mining analysis for malaria drug targets was conducted by integrating the three datasets, including GSE33811, GSE7586, and GSE5418. Limma package was used to detect differentially expressed genes (DEGs). The following cut-off criteria were used for screening DEGs: [log fold change (logFC)] > 1 and p-value < 0.05. This study employed a scoring system with seven criteria called functional annotations to prioritize the risk gene candidates for malaria. Following the scoring system, a score of> 2 was identified as a malaria biological risk gene. Overlapping analyses between gene target candidates and drug candidates were conducted using the DrugBank database to obtain new drug targets for malaria. Eighty drug-target genes were identified in this study, but only five genes exhibited druggability and overlapped with the targets of existing drugs, thereby presenting a potential avenue for malaria drug repurposing. These genes, namely PSMB2, CXCR4, ITGA4, RAF1, and PTGER3, hold promising prospects for malaria therapy. Interestingly, five genes were overlapped with 12 drug candidates (Sorafenib, Regorafenib, Dabrafenib, Natalizumab, Vedolizumab, Bimatoprost, Dinoprostone, Misoprostol, Gemeprost, Castor oil, Carfilzomib, and Plerixafor). In conclusion, an in-silico drug screening system not only can identify the biological risk genes but also potential to drives malaria drug repurposing.
- CXCR4
- drug repurposing
- ITGA4
- malaria
- PSMB2
- PTGER3
- transcriptomics
- RAF1
How to Cite
References
WHO. World malaria report 2022. World Health Organization: Geneva. (2022).
Mbeye NM, ter Kuile FO, Davies MA, Phiri KS, Egger M, Wandeler G, Ie DEASA. Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis. Trop Med Int Health (2014) 19 (9):1057-67.
Obonyo CO, Juma EA. Clindamycin plus quinine for treating uncomplicated falciparum malaria: a systematic review and meta-analysis. Malar J (2012) 11:2.
van Eijk AM, Terlouw DJ. Azithromycin for treating uncomplicated malaria. Cochrane Database Syst Rev (2011) 2011 (2):CD006688.
Pava Z, Puspitasari AM, Rumaseb A, Handayuni I, Trianty L, Utami RAS, Tirta YK, et al. Molecular surveillance over 14 years confirms reduction of Plasmodium vivax and falciparum transmission after implementation of Artemisinin-based combination therapy in Papua, Indonesia. PLoS Negl Trop Dis (2020) 14 (5):e0008295.
Sirota M, Dudley JT, Kim J, Chiang AP, Morgan AA, Sweet-Cordero A, Sage J, et al. Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci Transl Med (2011) 3 (96):96ra77.
Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov (2013) 12 (8):581-94.
Pessanha de Carvalho L, Kreidenweiss A, Held J. Drug Repurposing: A Review of Old and New Antibiotics for the Treatment of Malaria: Identifying Antibiotics with a Fast Onset of Antiplasmodial Action. Molecules (2021) 26 (8).
Yadav K, Shivahare R, Shaham SH, Joshi P, Sharma A, Tripathi R. Repurposing of existing therapeutics to combat drug-resistant malaria. Biomed Pharmacother (2021) 136:111275.
Ahmad SS, Rahi M, Saroha P, Sharma A. Ivermectin as an endectocide may boost control of malaria vectors in India and contribute to elimination. Parasit Vectors (2022) 15 (1):20.
Missinou MA, Borrmann S, Schindler A, Issifou S, Adegnika AA, Matsiegui PB, Binder R, et al. Fosmidomycin for malaria. Lancet (2002) 360 (9349):1941-2.
Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, et al. Metformin: Is it a drug for all reasons and diseases? Metabolism (2022) 133:155223.
Wang Y, Yella J, Jegga AG. Transcriptomic Data Mining and Repurposing for Computational Drug Discovery. Methods Mol Biol (2019) 1903:73-95.
Subudhi AK, Boopathi PA, Garg S, Middha S, Acharya J, Pakalapati D, Saxena V, et al. An in vivo transcriptome data set of natural antisense transcripts from Plasmodium falciparum clinical isolates. Genom Data (2014) 2:393-5.
Yao Y, Wu K, Xu M, Yang Y, Zhang Y, Yang W, Shang R, et al. Surveillance of Genetic Variations Associated with Antimalarial Resistance of Plasmodium falciparum Isolates from Returned Migrant Workers in Wuhan, Central China. Antimicrob Agents Chemother (2018) 62 (9).
Adikusuma W, Firdayani F, Irham LM, Darmawi D, Hamidy MY, Nopitasari BL, Soraya S, et al. Integrated genomic network analysis revealed potential of a druggable target for hemorrhoid treatment. Saudi Pharmaceutical Journal (2023) 31 (12):101831.
Adikusuma W, Zakaria ZA, Irham LM, Nopitasari BL, Pradiningsih A, Firdayani F, Septama AW, et al. Transcriptomics-driven drug repositioning for the treatment of diabetic foot ulcer. Scientific Reports (2023) 13 (1):10032.
Irham LM, Adikusuma W, La’ah AS, Chong R, Septama AW, Angelina M. Leveraging Genomic and Bioinformatic Analysis to Enhance Drug Repositioning for Dermatomyositis. Bioengineering (2023) 10 (8):890.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res (2013) 41 (Database issue):D991-5.
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature (2014) 506 (7488):376-81.
Adikusuma W, Chou WH, Lin MR, Ting J, Irham LM, Perwitasari DA, Chang WP, et al. Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis. Biomedicines (2022) 10 (1).
Afief AR, Irham LM, Adikusuma W, Perwitasari DA, Brahmadhi A, Cheung R. Integration of genomic variants and bioinformatic-based approach to drive drug repurposing for multiple sclerosis. Biochem Biophys Rep (2022) 32:101337.
Irham LM, Adikusuma W, Perwitasari DA. Genomic variants-driven drug repurposing for tuberculosis by utilizing the established bioinformatic-based approach. Biochem Biophys Rep (2022) 32:101334.
Irham LM, Adikusuma W, Perwitasari DA, Dania H, Maliza R, Faridah IN, Santri IN, et al. The use of genomic variants to drive drug repurposing for chronic hepatitis B. Biochem Biophys Rep (2022) 31:101307.
Santri IN, Irham LM, Djalilah GN, Perwitasari DA, Wardani Y, Phiri YVA, Adikusuma W. Identification of Hub Genes and Potential Biomarkers for Childhood Asthma by Utilizing an Established Bioinformatic Analysis Approach. Biomedicines (2022) 10 (9).
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res (2023) 51 (D1):D638-d646.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res (2018) 46 (D1):D1074-d1082.
National Center for Biotechnology Information. National Library of Medicine (US), National Center for Biotechnology Information. Bethesda (MD) (1988).
Zarin DA, Fain KM, Dobbins HD, Tse T, Williams RJ. 10-Year Update on Study Results Submitted to ClinicalTrials.gov. New England Journal of Medicine (2019) 381 (20):1966-1974.
Krupka M, Seydel K, Feintuch CM, Yee K, Kim R, Lin CY, Calder RB, et al. Mild Plasmodium falciparum malaria following an episode of severe malaria is associated with induction of the interferon pathway in Malawian children. Infect Immun (2012) 80 (3):1150-5.
Muehlenbachs A, Fried M, Lachowitzer J, Mutabingwa TK, Duffy PE. Genome-wide expression analysis of placental malaria reveals features of lymphoid neogenesis during chronic infection. J Immunol (2007) 179 (1):557-65.
Ockenhouse CF, Hu WC, Kester KE, Cummings JF, Stewart A, Heppner DG, Jedlicka AE, et al. Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. Infect Immun (2006) 74 (10):5561-73.
Sar P, Agarwal A, Vadodariya DH, Kariya H, Khuman J, Dalai S. MHC Class II (DRB) Promoter Polymorphism and Its Role in Parasite Control among Malaria Patients. J Immunol (2020) 204 (4):943-953.
Loughland JR, Minigo G, Sarovich DS, Field M, Tipping PE, Montes de Oca M, Piera KA, et al. Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation. Sci Rep (2017) 7 (1):2596.
Carpenter D, Abushama H, Bereczky S, Farnert A, Rooth I, Troye-Blomberg M, Quinnell RJ, et al. Immunogenetic control of antibody responsiveness in a malaria endemic area. Hum Immunol (2007) 68 (3):165-9.
Abrams ET, Brown H, Chensue SW, Turner GD, Tadesse E, Lema VM, Molyneux ME, et al. Host response to malaria during pregnancy: placental monocyte recruitment is associated with elevated beta chemokine expression. J Immunol (2003) 170 (5):2759-64.
Tovar Acero C, Ramirez-Montoya J, Velasco MC, Aviles-Vergara PA, Ricardo-Caldera D, Duran-Frigola M, Quintero G, et al. IL-4, IL-10, CCL2 and TGF-beta as potential biomarkers for severity in Plasmodium vivax malaria. PLoS Negl Trop Dis (2022) 16 (9):e0010798.
Wilson NO, Jain V, Roberts CE, Lucchi N, Joel PK, Singh MP, Nagpal AC, et al. CXCL4 and CXCL10 predict risk of fatal cerebral malaria. Dis Markers (2011) 30 (1):39-49.
Ruffner H, Bauer A, Bouwmeester T. Human protein-protein interaction networks and the value for drug discovery. Drug Discov Today (2007) 12 (17-18):709-16.
Suratanee A, Buaboocha T, Plaimas K. Prediction of Human-Plasmodium vivax Protein Associations From Heterogeneous Network Structures Based on Machine-Learning Approach. Bioinform Biol Insights (2021) 15:11779322211013350.
Li H, Ponder EL, Verdoes M, Asbjornsdottir KH, Deu E, Edgington LE, Lee JT, et al. Validation of the proteasome as a therapeutic target in Plasmodium using an epoxyketone inhibitor with parasite-specific toxicity. Chem Biol (2012) 19 (12):1535-45.
Kirkman LA, Zhan W, Visone J, Dziedziech A, Singh PK, Fan H, Tong X, et al. Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. Proc Natl Acad Sci U S A (2018) 115 (29):E6863-E6870.
Drosten M, Barbacid M. Targeting the MAPK Pathway in KRAS-Driven Tumors. Cancer Cell (2020) 37 (4):543-550.
Adderley JD, John von Freyend S, Jackson SA, Bird MJ, Burns AL, Anar B, Metcalf T, et al. Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention. Nat Commun (2020) 11 (1):4015.
Bando H, Pradipta A, Iwanaga S, Okamoto T, Okuzaki D, Tanaka S, Vega-Rodríguez J, et al. CXCR4 regulates Plasmodium development in mouse and human hepatocytes. J Exp Med (2019) 216 (8):1733-1748.
Kim J-Y, Kim H-H, Na B-K, Kim Y-J, Sohn Y, Kim H, Kim T-S, et al. Estimating the malaria transmission of Plasmodium vivax based on serodiagnosis. Malaria Journal (2012) 11 (1):257.
Li J, Liang X, Wang Q, Breyer RM, McCullough L, Andreasson K. Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia. Neurosci Lett (2008) 438 (2):210-5.
Riggle BA, Manglani M, Maric D, Johnson KR, Lee MH, Neto OLA, Taylor TE, et al. CD8+ T cells target cerebrovasculature in children with cerebral malaria. J Clin Invest (2020) 130 (3):1128-1138.
Reay WR, Cairns MJ. Advancing the use of genome-wide association studies for drug repurposing. Nat Rev Genet (2021) 22 (10):658-671.
Pathak V, Colah R, Ghosh K. Tyrosine kinase inhibitors: New class of antimalarials on the horizon? Blood Cells Mol Dis (2015) 55 (2):119-26.
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