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Targeted degradation of membrane and extracellular proteins with LYTACs

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Targeted protein degradation technology has gained substantial momentum over the past two decades as a revolutionary strategy for eliminating pathogenic proteins that are otherwise refractory to treatment. Among the various approaches developed to harness the body’s innate protein homeostasis mechanisms for this purpose, lysosome targeting chimeras (LYTACs) that exploit the lysosomal degradation pathway by coupling the target proteins with lysosome-trafficking receptors represent the latest innovation. These chimeras are uniquely tailored to degrade proteins that are membrane-bound and extracellular, encompassing approximately 40% of all proteome. Several novel LYTAC formulas have been developed recently, providing valuable insights for the design and development of therapeutic degraders. This review delineates the recent progresses of LYTAC technology, its practical applications, and the factors that dictate target degradation efficiency. The potential and emerging trends of this technology are discussed as well. LYTAC technology offers a promising avenue for targeted protein degradation, potentially revolutionizing the therapeutic landscape for numerous diseases.

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Fig. 1: Mechanism of membrane and extracellular protein degradation via LYTAC.
Fig. 2: First- and second-generation LYTAC technology.
Fig. 3: Targeted protein degradation by bispecific aptamer chimeras, covalent LYTACs, and apt-LYTACs.
Fig. 4: Mechanism of membrane protein degradation by ITAC, mITAC, and multivalent apt-LYTAC.
Fig. 5: Targeted protein degradation via KineTAC.
Fig. 6: Targeted protein degradation via LYTACA and nano-LYTAC.
Fig. 7: Targeted degradation of membrane and extracellular proteins by iLYTACs.

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References

  1. Zhang C, Liu Y, Li G, Yang Z, Han C, Sun X, et al. Targeting the undruggables-the power of protein degraders. Sci Bull. 2024;69:1776–97.

    Article  CAS  Google Scholar 

  2. Lu Y, Yang Y, Zhu G, Zeng H, Fan Y, Guo F, et al. Emerging pharmacotherapeutic strategies to overcome undruggable proteins in cancer. Int J Biol Sci. 2023;19:3360–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li Y, Song J, Zhou P, Zhou J, Xie S. Targeting undruggable transcription factors with PROTACs: Advances and perspectives. J Med Chem. 2022;65:10183–94.

    Article  CAS  PubMed  Google Scholar 

  4. Dale B, Cheng M, Park KS, Kaniskan H, Xiong Y, Jin J. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21:638–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang Z, Pang Q, Zhou J, Xuan C, Xie S. Leveraging aptamers for targeted protein degradation. Trends Pharmacol Sci. 2023;44:776–85.

    Article  CAS  PubMed  Google Scholar 

  6. Zhu H, Wang J, Zhang Q, Pan X, Zhang J. Novel strategies and promising opportunities for targeted protein degradation: an innovative therapeutic approach to overcome cancer resistance. Pharmacol Ther. 2023;244:108371.

    Article  CAS  PubMed  Google Scholar 

  7. Peng XP, Hu ZH, Zeng LM, Zhang MZ, Xu CC, Lu BY, et al. Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies. Acta Pharm Sin B. 2024;14:533–78.

    Article  CAS  PubMed  Google Scholar 

  8. Song J, Hu M, Zhou J, Xie S, Li T, Li Y. Targeted protein degradation in drug development: Recent advances and future challenges. Eur J Med Chem. 2023;261:115839.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang R, Xie S, Ran J, Li T. Restraining the power of proteolysis targeting chimeras in the cage: A necessary and important refinement for therapeutic safety. J Cell Physiol. 2024;239:e31255.

    Article  CAS  PubMed  Google Scholar 

  10. Huang D, Zou Y, Huang H, Yin J, Long S, Sun W, et al. A PROTAC augmenter for photo-driven pyroptosis in breast cancer. Adv Mater. 2024;36:e2313460.

    Article  PubMed  Google Scholar 

  11. Cai Z, Yang Z, Li H, Fang Y. Research progress of PROTACs for neurodegenerative diseases therapy. Bioorg Chem. 2024;147:107386.

    Article  CAS  PubMed  Google Scholar 

  12. Chen M, Zhou P, Kong Y, Li J, Li Y, Zhang Y, et al. Inducible degradation of oncogenic nucleolin using an aptamer-based PROTAC. J Med Chem. 2023;66:1339–48.

    Article  CAS  PubMed  Google Scholar 

  13. Kong L, Meng F, Wu S, Zhou P, Ge R, Liu M, et al. Selective degradation of the p53-R175H oncogenic hotspot mutant by an RNA aptamer-based PROTAC. Clin Transl Med. 2023;13:e1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhao L, Zhao J, Zhong K, Tong A, Jia D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022;7:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin J, Jin J, Shen Y, Zhang L, Gong G, Bian H, et al. Emerging protein degradation strategies: Expanding the scope to extracellular and membrane proteins. Theranostics. 2021;11:8337–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kong L, Meng F, Zhou P, Ge R, Geng X, Yang Z, et al. An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer. Sci Bull. 2024;69:2122–35.

    Article  CAS  Google Scholar 

  17. Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020;584:291–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021;17:937–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noblejas-López MDM, Tébar-García D, López-Rosa R, Alcaraz-Sanabria A, Cristóbal-Cueto P, Pinedo-Serrano A, et al. Tackling cancer by targeting selective protein degradation. Pharmaceutics. 2023;15:2442.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Miao Y, Gao Q, Mao M, Zhang C, Yang L, Yang Y, et al. Bispecific aptamer chimeras enable targeted protein degradation on cell membranes. Angew Chem Int Ed Engl. 2021;60:11267–71.

    Article  CAS  PubMed  Google Scholar 

  21. Wu Y, Lin B, Lu Y, Li L, Deng K, Zhang S, et al. Aptamer-LYTACs for targeted degradation of extracellular and membrane proteins. Angew Chem Int Ed Engl. 2023;62:e202218106.

    Article  CAS  PubMed  Google Scholar 

  22. Li Y, Liu X, Yu L, Huang X, Wang X, Han D, et al. Covalent LYTAC enabled by DNA aptamers for immune checkpoint degradation therapy. J Am Chem Soc. 2023;145:24506–21.

    CAS  Google Scholar 

  23. Tian Y, Miao Y, Guo P, Wang J, Han D. Insulin-like growth factor 2-tagged aptamer chimeras (ITACs) modular assembly for targeted and efficient degradation of two membrane proteins. Angew Chem Int Ed Engl. 2024;63:e202316089.

    Article  CAS  PubMed  Google Scholar 

  24. Duan Q, Jia HR, Chen W, Qin C, Zhang K, Jia F, et al. Multivalent aptamer-based lysosome-targeting chimeras (LYTACs) platform for mono- or dual-targeted proteins degradation on cell surface. Adv Sci. 2024;11:e2308924.

    Article  Google Scholar 

  25. Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano JC, Cotton AD, et al. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat Biotechnol. 2023;41:273–81.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Q, Yang X, Yuan R, Shen A, Wang P, Li H, et al. A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation. Nat Commun. 2024;15:1663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang K, Yu A, Liu K, Feng C, Hou Y, Chen J, et al. Nano-LYTACs for degradation of membrane proteins and inhibition of CD24/Siglec-10 signaling pathway. Adv Sci. 2023;10:e2305364.

    Article  Google Scholar 

  28. Zhang B, Brahma RK, Zhu L, Feng J, Hu S, Qian L, et al. Insulin-like growth factor 2 (IGF2)-fused lysosomal targeting chimeras for degradation of extracellular and membrane proteins. J Am Chem Soc. 2023;145:24272–83.

    Article  CAS  PubMed  Google Scholar 

  29. Su LY, Tian Y, Zheng Q, Cao Y, Yao M, Wang S, et al. Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor. Cell Chem Biol. 2024;31:1219–30.

    Article  CAS  PubMed  Google Scholar 

  30. Liu ZQ, Deng QQ, Qin G, Yang J, Zhang HC, Ren JS, et al. Biomarker-activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils. Chem-US. 2023;9:2016–38.

    Article  CAS  Google Scholar 

  31. Huang Y, Zhou X, Zhang Y, Xie M, Wang F, Qin J, et al. A nucleic acid-based LYTAC plus platform to simultaneously mediate disease-driven protein downregulation. Adv Sci. 2024;11:e2306248.

    Article  Google Scholar 

  32. Bagdanoff JT, Smith TM, Allan M, O’Donnell P, Nguyen Z, Moore EA, et al. Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands. Cell Chem Biol. 2023;30:97–109.

    Article  CAS  PubMed  Google Scholar 

  33. Ran J, Zhang Y, Zhang S, Li H, Zhang L, Li Q, et al. Targeting the HDAC6-cilium axis ameliorates the pathological changes associated with retinopathy of prematurity. Adv Sci. 2022;9:e2105365.

    Article  Google Scholar 

  34. Ran J, Guo G, Zhang S, Zhang Y, Zhang L, Li D, et al. KIF11 UFMylation maintains photoreceptor cilium integrity and retinal homeostasis. Adv Sci. 2024;11:e2400569.

    Article  Google Scholar 

  35. Hong R, Tan Y, Tian X, Huang Z, Wang J, Ni H, et al. XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis. EMBO Rep. 2024;25:1055–74.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Tan YJ, Jin Y, Zhou J, Yang YF. Lipid droplets in pathogen infection and host immunity. Acta Pharmacol Sin. 2024;45:449–64.

    Article  CAS  PubMed  Google Scholar 

  37. Sun S, Xu Z, Hu H, Zheng M, Zhang L, Xie W, et al. The Bacillus cereus toxin alveolysin disrupts the intestinal epithelial barrier by inducing microtubule disorganization through CFAP100. Sci Signal. 2023;16:eade8111.

    Article  CAS  PubMed  Google Scholar 

  38. Xie S, Li J, Sun S, Chen W, Cheng H, Song Y, et al. TUBright: a peptide probe for imaging microtubules. Anal Chem. 2022;94:11168–74.

    Article  CAS  PubMed  Google Scholar 

  39. Xu MM, Ryan P, Rudrawar S, Quinn RJ, Zhang HY, Mellick GD. Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein. Acta Pharmacol Sin. 2020;41:483–98.

    Article  CAS  PubMed  Google Scholar 

  40. Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, Bassik MC, et al. Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science. 2023;382:eadf6249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (32270892 and 32070708), and Henan Province Key Research and development and promotion special (Science and technology research): No. 242102311036.

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Authors and Affiliations

  1. Department of Clinical Pathobiology and Immunological Testing, School of Medical Laboratory, Qilu Medical University, Zibo, 255300, China

    Yu-yang Li

  2. Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Yang Yang

  3. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, 250014, China

    Ren-shuai Zhang & Rui-xin Ge

  4. Department of Ophthalmology, Tianjin Medical University General Hospital, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK “Belt and Road” Ophthalmology Joint Laboratory, Tianjin, 300052, China

    Song-bo Xie

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Correspondence to Yang Yang or Song-bo Xie.

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Li, Yy., Yang, Y., Zhang, Rs. et al. Targeted degradation of membrane and extracellular proteins with LYTACs. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01364-y

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