Structure, Function, and Clinical Relevance of Molecular Chaperones – A Review Article
Keywords:
Molecular chaperones, protein folding, proteostasisAbstract
Proteins known as molecular chaperones are essential components of cellular protein homeostasis since these proteins assist others in folding and stabilizing or degrading the polypeptides. The principle is that if misfolded or aggregated proteins—common in many pathologies such as cancer, neurodegenerative, and genetic diseases—are inhibited from forming deposits, then normal pathology can be restored. In general, chaperones have been recognized as significant targets and tools in clinical therapies due to their centrality towards proteostasis and thus provide room for innovation treatment approaches such as pharmacological chaperone therapy, chaperone inhibition, and gene-based enhancement strategies. Therefore, a deep insight into the structure and function of these proteins is paramount for safe and target-specific intervention development. The paper should try to convince the readers regarding the fact that though molecular chaperones possess all the requirements idealized theoretically to be applied clinically as therapeutic agents, there exist several practical obstacles that make this successful clinical application dubious.
References
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., ... & Suhr, O. B. (2018). Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. New England Journal of Medicine, 379(1), 11–21. https://doi.org/10.1056/NEJMoa1716153
Andtbacka, R. H. I., Kaufman, H. L., Collichio, F., Amatruda, T., Senzer, N., Chesney, J., Delman, K. A., Spitler, L. E., Puzanov, I., Agarwala, S. S., Milhem, M. M., Cranmer, L. D., Curti, B. D., Lewis, K. D., Ross, M., Guthrie, T., Linette, G. P., Daniels, G. A., Harrington, K., ... Coffin, R. S. (2015). Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. Journal of Clinical Oncology, 33(25), 2780–2788. https://doi.org/10.1200/JCO.2014.58.3377
Anzalone, A. V., Randolph, P. B., Davis, J. R., Sousa, A. A., Koblan, L. W., Levy, J. M., ... & Liu, D. R. (2020). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576(7785), 149–157. https://doi.org/10.1038/s41586-019-1711-4
Bacman, S. R., Kauppila, J. H. K., Pereira, C. V., Nissanka, N., Miranda, M., Pinto, M., ... & Moraes, C. T. (2018). MitoTALEN reduces mutant mtDNA load and restores tRNALys levels in a mouse model of mitochondrial disease. Nature Medicine, 24(11), 1696–1700. https://doi.org/10.1038/s41591-018-0165-7
Balazs, A. B., et al. (2014). Vectored antibody gene delivery protects against lethal influenza challenge in mice. Nature Biotechnology, 32(4), 384–388. https://doi.org/10.1038/nbt.2851
Barrangou, R., & Doudna, J. A. (2016). Applications of CRISPR technologies in research and beyond. Nature Biotechnology, 34(9), 933–941. https://doi.org/10.1038/nbt.3659
Cohen, S. N., Chang, A. C. Y., & Hsu, L. (1973). Nonchromosomal antibiotic resistance in bacteria: Genetic transformation of Escherichia coli by R-factor DNA. Proceedings of the National Academy of Sciences, 69(8), 2110–2114. https://doi.org/10.1073/pnas.69.8.2110
Cyranoski, D., & Ledford, H. (2018). Genome-edited baby claim provokes international outcry. Nature, 563(7733), 607–608. https://doi.org/10.1038/d41586-018-07545-0
Daley, G. Q., Lovell-Badge, R., & Steffann, J. (2019). After the storm—a responsible path for genome editing. New England Journal of Medicine, 380(10), 897–899. https://doi.org/10.1056/NEJMp1900504
Doudna, J. A., & Charpentier, E. (2014). Genome editing: The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213). https://doi.org/10.1126/science.1258096
Fesnak, A. D., June, C. H., & Levine, B. L. (2016). Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer, 16(9), 566–581. https://doi.org/10.1038/nrc.2016.97
Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y. S., Domm, J., Eustace, B. K., ... & Corbacioglu, S. (2021). CRISPR–Cas9 gene editing for sickle cell disease and β-thalassemia. New England Journal of Medicine, 384(3), 252–260. https://doi.org/10.1056/NEJMoa2031054
Gaj, T., Gersbach, C. A., & Barbas, C. F. (2013). ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends in Biotechnology, 31(7), 397–405. https://doi.org/10.1016/j.tibtech.2013.04.004
Gantz, V. M., Jasinskiene, N., Tatarenkova, O., Fazekas, A., Macias, V. M., Bier, E., & James, A. A. (2015). Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. Proceedings of the National Academy of Sciences, 112(49), E6736–E6743. https://doi.org/10.1073/pnas.1521077112
Gyngell, C., Douglas, T., & Savulescu, J. (2017). The ethics of germline gene editing. Journal of Applied Philosophy, 34(4), 498–513. https://doi.org/10.1111/japp.12249
High, K. A., & Roncarolo, M. G. (2019). Gene therapy. New England Journal of Medicine, 381(5), 455–464. https://doi.org/10.1056/NEJMra1706910
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816–821. https://doi.org/10.1126/science.1225829
June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S., & Milone, M. C. (2018). CAR T cell immunotherapy for human cancer. Science, 359(6382), 1361–1365. https://doi.org/10.1126/science.aar6711
Kaminski, R., Bella, R., Yin, C., Otte, J., Ferrante, P., Gendelman, H. E., Li, H., Burdo, T. H., McMillan, J., Afonso, P. V., Chaudhry, A., Beilman, G. J., Hu, W., & Khalili, K. (2016). Excision of HIV-1 DNA by CRISPR-Cas9: A proof-of-concept in vivo study. Gene Therapy, 23(8–9), 690–695. https://doi.org/10.1038/gt.2016.41
Kim, J. H., Kim, M., Kim, S., & Kim, J. S. (2022). Genomic editing tools and their medical applications. Experimental & Molecular Medicine, 54(5), 689–703. https://doi.org/10.1038/s12276-022-00767-7
Leibman, R. S., Richardson, M. W., Ellebrecht, C. T., Maldini, C. R., Glover, J. A., Secreto, A. J., Kulikovskaya, I., Lacey, S. F., Akkina, R., Yi, Y., Collman, R. G., Riley, J. L., Ruella, M., Barrett, D. M., Grupp, S. A., June, C. H., Gill, S., Porter, D. L., Jacobson, J. M., … Riley, J. L. (2017). Supraphysiologic control over HIV-1 replication mediated by CD8+ T cells expressing a re-engineered CD4-based chimeric antigen receptor. Journal of Virology, 91(4), e01937–16. https://doi.org/10.1128/JVI.01937-16
Lino, C. A., Harper, J. C., Carney, J. P., & Timlin, J. A. (2018). Delivering CRISPR: a review of the challenges and approaches. Drug Delivery, 25(1), 1234–1257. https://doi.org/10.1080/10717544.2018.1474964
Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., Bader, P., Verneris, M. R., Stefanski, H. E., Myers, G. D., De Moerloose, B., Hiramatsu, H., Schlis, K., Davis, K. L., Martin, P. L., Nemecek, E. R., Yanik, G. A., Peters, C., Baruchel, A., … Grupp, S. A. (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), 439–448. https://doi.org/10.1056/NEJMoa1709866
Mendell, J. R., Al-Zaidy, S., Shell, R., Arnold, W. D., Rodino-Klapac, L. R., Prior, T. W., ... & Kissel, J. T. (2017). Single-dose gene-replacement therapy for spinal muscular atrophy. New England Journal of Medicine, 377(18), 1713–1722. https://doi.org/10.1056/NEJMoa1706198
Mimee, M., Tucker, A. C., Voigt, C. A., & Lu, T. K. (2016). Programming a human commensal bacterium, Bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. Cell Systems, 1(1), 62–71. https://doi.org/10.1016/j.cels.2015.06.001
Mullard, A. (2020). Gene-editing therapies head into clinic. Nature Reviews Drug Discovery, 19(6), 351–352. https://doi.org/10.1038/d41573-020-00074-9
Naldini, L. (2015). Gene therapy returns to centre stage. Nature, 526(7573), 351–360. https://doi.org/10.1038/nature15818
Nelson, C. E., Hakim, C. H., Ousterout, D. G., Thakore, P. I., Moreb, E. A., Castellanos Rivera, R. M., ... & Gersbach, C. A. (2016). In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science, 351(6271), 403–407. https://doi.org/10.1126/science.aad5143
Niemann, H. H., Liu, Y., & Timmis, K. N. (2021). Genetic engineering: Past achievements and future prospects. Current Opinion in Biotechnology, 70, 1–8. https://doi.org/10.1016/j.copbio.2020.09.001
Ott, P. A., Hu, Z., Keskin, D. B., Shukla, S. A., Sun, J., Bozym, D. J., Zhang, W., Luoma, A., Giobbie-Hurder, A., Peter, L., Chen, C., Olive, O., Carter, T. A., Li, S., Lieb, D. J., Eisenhaure, T., Gjini, E., Stevens, J., Lane, W. J., … Wu, C. J. (2017). An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 547(7662), 217–221. https://doi.org/10.1038/nature22991
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines — a new era in vaccinology. Nature Reviews Drug Discovery, 17(4), 261–279. https://doi.org/10.1038/nrd.2017.243
Pasi, K. J., Rangarajan, S., Mitchell, N., Lester, W., Symington, E., Madan, B., ... & Pierce, G. F. (2020). Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. New England Journal of Medicine, 382(1), 29–40. https://doi.org/10.1056/NEJMoa1908490
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., ... & Gruber, W. C. (2020). Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. New England Journal of Medicine, 383(27), 2603–2615. https://doi.org/10.1056/NEJMoa2034577
Rainov, N. G. (2000). A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Human Gene Therapy, 11(17), 2389–2401. https://doi.org/10.1089/104303400750035611
Rosenberg, S. A., & Restifo, N. P. (2015). Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348(6230), 62–68. https://doi.org/10.1126/science.aaa4967
Rupp, L. J., Schumann, K., Roybal, K. T., Gate, R. E., Ye, C. J., Lim, W. A., & Marson, A. (2017). CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific Reports, 7(1), 737. https://doi.org/10.1038/s41598-017-00462-8
Russell, S. J., Peng, K. W., & Bell, J. C. (2012). Oncolytic virotherapy. Nature Biotechnology, 30(7), 658–670. https://doi.org/10.1038/nbt.2287
Tabrizi, S. J., Leavitt, B. R., Landwehrmeyer, G. B., Wild, E. J., Saft, C., Barker, R. A., ... & Lane, R. M. (2019). Targeting huntingtin expression in patients with Huntington’s disease. New England Journal of Medicine, 380(24), 2307–2316. https://doi.org/10.1056/NEJMoa1900907
Yang, S., Chang, R., Yang, H., Zhao, T., Hong, Y., Kong, H. E., ... & Li, S. (2017). CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. Journal of Clinical Investigation, 127(7), 2719–2724. https://doi.org/10.1172/JCI92087
Yazawa, K., Fujimura, K., Koyama, Y., Nishikawa, S., & Shibata, H. (2020). Bacterial cancer therapy: engineering bacteria as anti-cancer agents. Frontiers in Oncology, 10, 297. https://doi.org/10.3389/fonc.2020.00297
