Drug repurposing for glomerular diseases: an underutilized resource

Waring, M. J. et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug. Discov. 14, 475–486 (2015). In-depth analysis of attrition data of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer demonstrating that safety and toxicology are the greatest sources of failure.

Article  CAS  PubMed  Google Scholar 

Papapetropoulos, A. & Szabo, C. Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br. J. Pharmacol. 175, 165–167 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Smerud, H. K. et al. New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria. Nephrol. Dial. Transpl. 26, 3237–3242 (2011).

Article  CAS  Google Scholar 

Kiryluk, K. et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat. Genet. 46, 1187–1196 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

U.S. Food and Drug Administration. Drugs@FDA:FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm (2024).

Liu, D. et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin. Immunol. 9, 30 (2013).

Article  PubMed  PubMed Central  Google Scholar 

Hogan, S. L. et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann. Intern. Med. 143, 621–631, (2005).

Article  PubMed  Google Scholar 

Yu, C.-C. et al. Abatacept in B7-1-positive proteinuric kidney disease. N. Engl. J. Med. 369, 2416–2423 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pushpakom, S. et al. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 18, 41–58 (2019). Comprehensive discussion of methods for identifying drug candidates for repurposing.

Article  CAS  PubMed  Google Scholar 

Huang, H.-J. et al. Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor. Comput. Struct. Biotechnol. J. 21, 3490–3502 (2023). Example of molecular docking analysis being used to identify ritodrine, dofetilide, dobutamine and citalopram as ligands for prostaglandin E2 receptor to attenuate kidney fibrosis.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kharkar, P. S., Warrier, S. & Gaud, R. S. Reverse docking: a powerful tool for drug repositioning and drug rescue. Future Med. Chem. 6, 333–342 (2014).

Article  CAS  PubMed  Google Scholar 

Warren, G. L. et al. A critical assessment of docking programs and scoring functions. J. Med. Chem. 49, 5912–5931 (2006).

Article  CAS  PubMed  Google Scholar 

Vidović, D., Koleti, A. & Schürer, S. C. Large-scale integration of small molecule-induced genome-wide transcriptional responses, Kinome-wide binding affinities and cell-growth inhibition profiles reveal global trends characterizing systems-level drug action. Front. Genet. 5, 342 (2014).

PubMed  PubMed Central  Google Scholar 

Xia, M. et al. Identification of hub genes and therapeutic agents for IgA nephropathy through bioinformatics analysis and experimental validation. Front. Med. 9, 881322 (2022). Example of how drug–disease signature matching using data from Connectivity Map identified tetrandrine as a candidate to reverse IgAN differential expression profile.

Article  Google Scholar 

Xu, W. et al. Tetrandrine inhibits the proliferation of mesangial cells induced by enzymatically deglycosylated human IgA1 via IgA receptor/MAPK/NF-κB signaling pathway. Front. Pharmacol. 14, 1150829 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Subramanian, A. et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437–1452.e1417 (2017). Report of L1000 — a low-cost, high-throughput reduced representation expression profiling method for assessing the transcription profile of cells after treatment with a perturbagen.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lim, N. & Pavlidis, P. Evaluation of connectivity map shows limited reproducibility in drug repositioning. Sci. Rep. 11, 17624 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Campillos, M., Kuhn, M., Gavin, A.-C., Jensen, L. J. & Bork, P. Drug target identification using side-effect similarity. Science 321, 263–266 (2008).

Article  CAS  PubMed  Google Scholar 

Gaspar, H. A. et al. Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder. Transl. Psychiatry 9, 117 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Laudisio, A. et al. Use of proton-pump inhibitors is associated with depression: a population-based study. Int. Psychogeriatr. 30, 153–159 (2018).

Article  PubMed  Google Scholar 

Gebeshuber, C. A. et al. Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis. Transl. Res. 259, 28–34 (2023). Example of pathway mapping being used to identify clopidogrel as a drug repurposing candidate for FSGS.

Article  CAS  PubMed  Google Scholar 

Daniel-Fischer, L. et al. Clopidogrel for proteinuria reduction in focal segmental glomerulosclerosis: phase 2 trial design. Kidney Int. Rep. 9, 478–481 (2024).

Article  PubMed  Google Scholar 

Jung, K. et al. Automated detection of off-label drug use. PLoS One 9, e89324 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Kim, S. et al. Automatic extraction of comprehensive drug safety information from adverse drug event narratives in the Korea adverse event reporting system using natural language processing techniques. Drug. Saf. 46, 781–795 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64, 1215–1226 (2012).

Article  CAS  PubMed  Google Scholar 

Fernández-Juárez, G. et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int. 99, 986–998 (2021).

Article  PubMed  Google Scholar 

Katikaneni, D., Morel, L. & Scindia, Y. Animal models of lupus nephritis: the past, present and a future outlook. Autoimmunity 57, 2319203 (2024).

Article  PubMed  Google Scholar 

Dvela-Levitt, M. et al. Small molecule targets TMED9 and promotes lysosomal degradation to reverse proteinopathy. Cell 178, 521–535.e523 (2019). Seminal study that involved the development of an automated high-throughput cellular assay that identified BRD4780 for the treatment of MUC1 nephropathy.

Article  CAS  PubMed  Google Scholar 

Tran, T. et al. A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery. Cell Stem Cell 29, 1083–1101.e7 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kroll, K. T. et al. Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies. Proc. Natl Acad. Sci. USA 120, e2305322120 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Han, J. J. FDA modernization Act 2.0 allows for alternatives to animal testing. Artif. Organs 47, 449–450 (2023).

Article  PubMed  Google Scholar 

Anders, H.-J., Kitching, A. R., Leung, N. & Romagnani, P. Glomerulonephritis: immunopathogenesis and immunotherapy. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00816-y (2023). Insightful discussion of immunological mechanisms driving glomerular diseases and pathobiology-directed glomerular disease taxonomy.

Comments (0)

No login
gif