γ-secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-secretase Review
| Authors: | Nie, P.; Vartak, A.; Li, Y. M. |
| Review Title: | γ-secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-secretase |
| Abstract: | Over two decades, γ-secretase has been the target for extensive therapeutic development due to its pivotal role in pathogenesis of Alzheimer's disease and cancer. However, it has proven to be a challenging task owing to its large set of substrates and our limited understanding of the enzyme's structural and mechanistic features. The scientific community is taking bigger strides towards solving this puzzle with recent advancement in techniques like cryogenic electron microscopy (cryo-EM) and photo-affinity labelling (PAL). This review highlights the significance of the PAL technique with multiple examples of photo-probes developed from γ-secretase inhibitors and modulators. The binding of these probes into active and/or allosteric sites of the enzyme has provided crucial information on the γ-secretase complex and improved our mechanistic understanding of this protease. Combining the knowledge of function and regulation of γ-secretase will be a decisive factor in developing novel γ-secretase modulators and biological therapeutics. © 2020 |
| Keywords: | review; nonhuman; electron microscopy; complex formation; inhibitor; enzyme regulation; regulatory mechanism; sulfonamide; nonsteroid antiinflammatory agent; enzyme binding; alzheimer disease; gamma secretase inhibitor; gamma secretase; enzyme active site; carboxylic acid; affinity labeling; mechanism; clinical trial (topic); allosteric site; imidazole; γ-secretase; modulator; human; photo affinity labeling |
| Journal Title: | Seminars in Cell and Developmental Biology |
| Volume: | 105 |
| ISSN: | 1084-9521 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-09-01 |
| Start Page: | 43 |
| End Page: | 53 |
| Language: | English |
| DOI: | 10.1016/j.semcdb.2020.03.002 |
| PUBMED: | 32249070 |
| PROVIDER: | scopus |
| PMCID: | PMC7483676 |
| DOI/URL: | |
| Notes: | Review -- Export Date: 1 October 2020 -- Source: Scopus |
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