PROTACs and Other Chemical Protein Degradation Technologies for the Treatment of Neurodegenerative Disorders

Abstract

Neurodegenerative disorders (NDs) are a group of diseases that cause neural cell damage, leading to motility and/or cognitive dysfunctions. One of the causative agents is misfolded protein aggregates, which are considered as undruggable in terms of conventional tools, such as inhibitors and agonists/antagonists. Indeed, there is currently no FDA‐approved drug for the causal treatment of NDs. However, emerging technologies for chemical protein degradation are opening up the possibility of selective elimination of target proteins through physiological protein degradation machineries, which do not depend on the functions of the target proteins. Here, we review recent efforts towards the treatment of NDs using chemical protein degradation technologies, and we briefly discuss the challenges and prospects.

Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo

“…The use of PROTACs, as an emerging small-molecule knockdown strategy, has gained considerable attention in both academia and the pharmaceutical industry as means of expanding therapeutic landscapes not accessible to conventional drugs 31 , 32 , 33 , 34 , 35 . To date, this rapidly developed technique has been successfully employed for the degradation of various proteins involved in cancer 37 , 38 , 39 , 40 and neurodegenerative diseases 54 , 55 , including nuclear receptors 56 , 57 , kinases 58 , 59 , 60 , epigenetic readers 61 , 62 , 63 and transcription factors 64 . On the other hand, statin-induced compensatory upregulation of HMGCR (an ER transmembrane protein), a common phenomenon 13 , 14 , 15 , 16 , decreases statin sensitivity and leads to higher dose requirements that unavoidably cause high risks of side effects 17 , 18 .…”

Selenium Nanoparticles as Candidates for Antibacterial Substitutes and Supplements against Multidrug-Resistant Bacteria

“…A recent paradigm of drug discovery involves the identification of substances that can target proteins [63][64][65]. However, such studies on antibacterial agents are lacking.…”

Bispecific Aptamer Chimeras Enable Targeted Protein Degradation on Cell Membranes

“…Cell‐membrane‐bound proteins play important roles in regulating functions of cells and therefore are crucial therapeutic sites for various diseases such as cancer and immune‐related disorders [1, 2] . Methods that can rapidly and efficiently reduce the effective abundance of membrane proteins, including function inhibition, sequestration, downregulation or degradation, will benefit the development of therapeutic strategies towards membrane protein targets and thus improve human health [3, 4] …”

“…[1,2] Methods that can rapidly and efficiently reduce the effective abundance of membrane proteins, including function inhibition, sequestration, downregulation or degradation, will benefit the development of therapeutic strategies towards membrane protein targets and thus improve human health. [3,4] One type of strategies that control the targeted membrane protein abundance mainly rely on genetic expression perturbations such as regulating messenger RNAs (mRNAs) to inhibit their translation or lead to RNA degradation by cellular quality control systems. [5,6] However, the applications of these genetic engineering methods are restricted by limitations such as their time-consuming nature, unpredictability and inefficiency.…”