Drug Repurposing: An Overview
Drug repurposing (also known as drug repositioning) means finding novel indications for currently marketed drugs. This strategy may reduce the costs of new drug development and advance the delivery of new therapeutics to patients with incurable diseases. By specifically regulating multiple targets, more effective drugs can be developed through polypharmacology. Drug repositioning is underpinned by the fact that common molecular pathways contribute to many different diseases. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing, discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.
2. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM. et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996; 8:47-52
3. McBride WG. Thalidomide embryopathy. Teratology. 1977; 16:79-82
4. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994; 91:4082-5
5. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999; 341:1565-71
6. Ning YM, Gulley JL, Arlen PM, Woo S, Steinberg SM, Wright JJ. et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:2070-6
7. Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019; 18:41–58.
8. Witkowski TX. Intellectual property and other legal aspects of drug repurposing. Drug Discov Today Ther Strateg. 2011; 8(3–4):139–143.
9. Breckenridge A, Jacob R. Overcoming the legal and regulatory barriers to drug repurposing. Nat Rev Drug Discov. 2019; 18:1–2.
10. Allarakhia M. Open-source approaches for the repurposing of existing or failed candidate drugs: learning from and applying the lessons across diseases. Drug Des Devel Ther. 2013; 7:753–766.
11. Ritchie MD, Holzinger ER, Li R, et al. Methods of integrating data to uncover genotype-phenotype interactions. Nat Rev Genet. 2015; 16:85–97.
12. McKerrow JH, Doyle PS, Engel JC, et al. Two approaches to discovering and developing new drugs for Chagas disease. Mem Inst Oswaldo Cruz. 2009; 104(Suppl 1):263–269
13. Engel JC, Ang KKH, Chen S, et al. Image-based high-throughput drug screening targeting the intracellular stage of Trypanosoma cruzi, the agent of Chagas’ disease. Antimicrob Agents Chemother. 2010; 54:3326–3334.
14. Planer JD, Hulverson MA, Arif JA, et al. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl Trop Dis. 2014; 8(7):e2977.
15. Sykes ML, Avery VM. Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes. Int J Parasitol Drugs Drug Resist. 2015; 5(3):215–228.
16. Hammond DJ, Cover B, Gutteridge WW. A novel series of chemical structures active in vitro against the trypomastigote form of Trypanosoma cruzi. Trans R Soc Trop Med Hyg. 1984; 78:91–95.
17. Hammond DJ, Hogg J, Gutteridge WE. Trypanosoma cruzi: possible control of parasite transmission by blood transfusion using amphiphilic cationic drugs. Exp Parasitol. 1985; 60:32–34.
18. Bellera CL, Balcazar DE, Vanrell MC, et al. Computer-guided drug repurposing: identification of trypanocidal activity of clofazimine, benidipine and saquinavir. Eur J Med Chem. 2015; 93:338–348.
19. Alberca LN, Sbaraglini ML, Morales JF, et al. Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake. Front Cell Infect Microbiol. 2018; 8:173.
20. Alirol E, Schrumpf D, Amici Heradi J, et al. Nifurtimox-eflornithine combination therapy for second-stage gambiense human African trypanosomiasis: Médecins Sans Frontières experience in the democratic republic of the Congo. Clin Infect Dis. 2013; 56(2):195–203.
21. Yan, X.-Y., Zhang, S.-W. & He, C.-R. Prediction of drug-target interaction by integrating diverse heterogeneous information source with multiple kernel learning and clustering methods. Computational Biology and Chemistry 78, 460–467 (2019).
22. Yamanishi, Y., Kotera, M., Kanehisa, M. & Goto, S. Drug-target interaction prediction from chemical, genomic and pharmacological data in an integrated framework. Bioinformatics 26, i246–254 (2010).
23. Klabunde, T. & Hessler, G. Drug design strategies for targeting g-protein-coupled receptors. ChemBioChem 3, 928–944 (2002).
24. Yan, X.-Y., Zhang, S.-W. & Zhang, S.-Y. Prediction of drug–target interaction by label propagation with mutual interaction information derived from heterogeneous network. Mol. BioSyst. 12, 520–531 (2016).
25. Ding, H., Takigawa, I., Mamitsuka, H. & Zhu, S. Similarity-based machine learning methods for predicting drug-target interactions: a brief review. Brief. Bioinformatics 15, 734–747 (2014).
26. Pahikkala, T. et al. Toward more realistic drug-target interaction predictions. Brief. Bioinformatics 16, 325–337 (2015).
27. Haupt, V. J. et al. Computational drug repositioning by target hopping: A use case in chagas disease. Current Pharmaceutical Design 22, 3124–3134 (2016).
28. Li, Y. Y., An, J. & Jones, S. J. M. A computational approach to finding novel targets for existing drugs. PLOS Computational Biology 7, 1–13 (2011). URL https://doi.org/10.1371/journal.pcbi.1002139.
29. Kinnings, S. L. et al. Drug discovery using chemical systems biology: Repositioning the safe medicine comtan to treat multi-drug and extensively drug resistant tuberculosis. PLOS Computational Biology 5, 1–10 (2009). URL https://doi.org/10.1371/journal.pcbi.1000423.
30. Dakshanamurthy, S. et al. Predicting new indications for approved drugs using a proteochemometric method. Journal of Medicinal Chemistry 55, 6832–6848 (2012).
31. https://doi.org/10.1021/jm300576q. PMID: 22780961, https://doi.org/10.1021/jm300576q.
32. Peng, Y. et al. 5-ht2c receptor structures reveal the structural basis of gpcr polypharmacology. Cell 172, 719–730.e14 (2018).
33. Salentin, S. et al. From malaria to cancer: Computational drug repositioning of amodiaquine using PLIP interaction patterns. Sci Rep 7, 11401 (2017).
34. Pollastri MP. Fexinidazole: a new drug for african sleeping sickness on the horizon. Trends Parasitol. 2018; 34:178–179.
35. Garrido P, Aldaz A, Vera R, et al. Proposal for the creation of a national strategy for precision medicine in cancer: a position statement of SEOM, SEAP, and SEFH. Clin Transl Oncol. 2017;41(6):688–691.
36. Jones MR, Schrader KA, Shen Y, et al. Response to angiotensin blockade with irbesartan in a patient with metastatic colorectal cancer. Ann Oncol. 2016; 27(7):801–806.
37. Sun W 1, Sanderson PE, Zheng W. Drug combination therapy increases successful drug repositioning. Drug Discov Today. 2016; 21(7):1189–1195.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
AUTHORS WHO PUBLISH WITH THIS JOURNAL AGREE TO THE FOLLOWING TERMS:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).