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Advanced Neurology Brain bioavailability of targeted protein degraders

could be more challenging due to the anatomically tight Consent for publication
and intact BBB, characterized by the high density of tight
junctions and proteins. The BBB in younger individuals Not applicable.
offers high resistance to macromolecule permeation, Availability of data
posing a significant challenge in achieving sufficient TPD
delivery across the barrier – an issue that has historically Not applicable.
hindered many small molecule pre-clinical drugs from
reaching their CNS targets, thus limiting their therapeutic References
efficacy. 1. Pajouhesh H, Lenz GR. Medicinal chemical properties
of successful central nervous system drugs. NeuroRx.
However, there is still a long way to go before we can
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the BBB within the therapeutic window, as well as assess any doi: 10.1602/neurorx.2.4.541
potential spillover into the neurotoxicity zone if any, while 2. Fong CW. Permeability of the blood brain barrier: Molecular
evaluating BBB permeability. Unraveling the mechanisms mechanism of transport of drugs and physiologically
and routes that TPDs use to permeate the BBB could help important compounds. J Membr Biol. 2015;248(4):651-669.
address this issue. Given the number of TPDs undergoing doi: 10.1007/s00232-015-9778-9
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understanding the underlying mechanisms will pave the way 3. Pardridge WM. The blood-brain barrier: Bottleneck in brain
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Acknowledgments bioavailable and blood brain barrier penetrant PROTAC
The authors deeply appreciate the support of Aragen’s degrader of leucine rich repeat kinase 2. J Am Chem Soc.
corporate communications team (Apoorva Kadlag and 2022;144(37):16930-16952.
Dr. Anuja Bhardwaj) for their assistance with graphic doi: 10.1021/jacs.2c05499
design. The authors also thank Dr. Anuja Bhardwaj 5. Catarina Silva M, Ferguson FM, Cai Q, et al. Targeted
for proofreading the final draft and providing valuable degradation of aberrant tau in frontotemporal dementia
feedback and suggestions. patient-derived neuronal cell models. Elife. 2019;8:e45457.

Funding doi: 10.7554/eLife.45457
None. 6. Wang W, Zhou Q, Jiang T, et al. A novel small-molecule
PROTAC selectively promotes tau clearance to improve
Conflict of interest cognitive functions in Alzheimer-like models. Theranostics.
2021;11(11):5279-5295.
Satinder Singh, Satish Kumar, and Pratima Srivastava
are employees of Aragen Life Sciences Limited. Vyas M. doi: 10.7150/thno.55680
Shingatgeri is the Dean of the School of Biosciences at 7. Risser L, Plouraboué F, Cloetens P, Fonta C.
Apeejay Stya University. The authors declare that they A 3D-investigation shows that angiogenesis in primate
have no known competing financial interests or personal cerebral cortex mainly occurs at capillary level. Int J Dev
relationships that could have influenced the work reported Neurosci. 2009;27(2):185-196.
in this article. doi: 10.1016/j.ijdevneu.2008.10.006

Author contributions 8. Risser L, Plouraboué F, Steyer A, Cloetens P, Duc CL,
Fonta C. From homogeneous to fractal normal and
Conceptualization: Satinder Singh tumorous microvascular networks in the brain. J Cereb
Visualization: Satinder Singh, Satish Saini Blood Flow Metab. 2007;27(2):293-303.
Writing – original draft: Satinder Singh doi: 10.1038/sj.jcbfm.9600332
Writing – review & editing: Vyas M. Shingatgeri, Pratima 9. Heinzer S, Kuhn G, Krucker T, et al. Novel three-dimensional
Srivastava
analysis tool for vascular trees indicates complete micro-
Ethics approval and consent to participate networks, not single capillaries, as the angiogenic endpoint
in mice overexpressing human VEGF (165) in the brain.
Not applicable. Neuroimage. 2008;39(4):1549-1558.

Volume 4 Issue 2 (2025) 71 doi: 10.36922/an.5140