Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins

Chenghong Zhu

State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023 China

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Weishan Wang,

Weishan Wang

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Yan Wang,

Yan Wang

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Prof. Yan Zhang,

Corresponding Author

Prof. Yan Zhang

[email protected]

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Prof. Jinbo Li,

Corresponding Author

Prof. Jinbo Li

[email protected]

orcid.org/0000-0002-7875-4369

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Chenghong Zhu,

Chenghong Zhu

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Weishan Wang,

Weishan Wang

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Yan Wang,

Yan Wang

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Prof. Yan Zhang,

Corresponding Author

Prof. Yan Zhang

[email protected]

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Prof. Jinbo Li,

Corresponding Author

Prof. Jinbo Li

[email protected]

orcid.org/0000-0002-7875-4369

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First published: 03 February 2023

https://doi.org/10.1002/ange.202300694

Abstract

Bispecific chimeras bridging cell membrane proteins with lysosome-trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease-relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain-promoted alkyne-azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti-cancer application of NCL-targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.

Open Research

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supporting Information

References

1
1aF. Weiss, D. Lauffenburger, P. Friedl, Nat. Rev. Cancer 2022, 22, 157–173;
10.1038/s41568-021-00427-0
CAS PubMed Web of Science® Google Scholar
1bN. D. Huntington, J. Cursons, J. Rautela, Nat. Rev. Cancer 2020, 20, 437–454.
10.1038/s41568-020-0272-z
CAS PubMed Web of Science® Google Scholar
2B. Dale, M. Cheng, K. S. Park, H. U. Kaniskan, Y. Xiong, J. Jin, Nat. Rev. Cancer 2021, 21, 638–654.
10.1038/s41568-021-00365-x
CAS PubMed Web of Science® Google Scholar
3K. M. Sakamoto, K. B. Kim, A. Kumagai, F. Mercurio, C. M. Crews, R. J. Deshaies, Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559.
10.1073/pnas.141230798
CAS PubMed Web of Science® Google Scholar
4
4aA. D. Cotton, D. P. Nguyen, J. A. Gramespacher, I. B. Seiple, J. A. Wells, J. Am. Chem. Soc. 2021, 143, 593–598;
10.1021/jacs.0c10008
CAS PubMed Web of Science® Google Scholar
4bJ. A. Gramespacher, A. D. Cotton, P. W. W. Burroughs, I. B. Seiple, J. A. Wells, ACS Chem. Biol. 2022, 17, 1259–1268;
10.1021/acschembio.2c00185
CAS PubMed Web of Science® Google Scholar
4cH. Marei, W. K. Tsai, Y. S. Kee, K. Ruiz, J. He, C. Cox, T. Sun, S. Penikalapati, P. Dwivedi, M. Choi, D. Kan, P. Saenz-Lopez, K. Dorighi, P. Zhang, Y. T. Kschonsak, N. Kljavin, D. Amin, I. Kim, A. G. Mancini, T. Nguyen, C. Wang, E. Janezic, A. Doan, E. Mai, H. Xi, C. Gu, M. Heinlein, B. Biehs, J. Wu, I. Lehoux, S. Harris, L. Comps-Agrar, D. Seshasayee, F. J. de Sauvage, M. Grimmer, J. Li, N. J. Agard, E. M. F. de Sousa, Nature 2022, 610, 182–189;
10.1038/s41586-022-05235-6
CAS PubMed Web of Science® Google Scholar
4dK. Pance, J. A. Gramespacher, J. R. Byrnes, F. Salangsang, J. C. Serrano, A. D. Cotton, V. Steri, J. A. Wells, Nat. Biotechnol. 2022, https://doi.org/10.1038/s41587-022-01456-2.
10.1038/s41587-022-01456-2
PubMed Web of Science® Google Scholar
5H. Zhang, Y. Han, Y. Yang, F. Lin, K. Li, L. Kong, H. Liu, Y. Dang, J. Lin, P. R. Chen, J. Am. Chem. Soc. 2021, 143, 16377–16382.
10.1021/jacs.1c08521
CAS PubMed Web of Science® Google Scholar
6G. Ahn, S. M. Banik, C. R. Bertozzi, Cell Chem. Biol. 2021, 28, 1072–1080.
10.1016/j.chembiol.2021.02.024
CAS PubMed Web of Science® Google Scholar
7
7aS. M. Banik, K. Pedram, S. Wisnovsky, G. Ahn, N. M. Riley, C. R. Bertozzi, Nature 2020, 584, 291–297;
10.1038/s41586-020-2545-9
CAS PubMed Web of Science® Google Scholar
7bY. Miao, Q. Gao, M. Mao, C. Zhang, L. Yang, Y. Yang, D. Han, Angew. Chem. Int. Ed. 2021, 60, 11267–11271;
10.1002/anie.202102170
CAS PubMed Web of Science® Google Scholar
Angew. Chem. 2021, 133, 11367–11371;
10.1002/ange.202102170
Web of Science® Google Scholar
7cX. Zhang, H. Liu, J. He, C. Ou, T. C. Donahue, M. M. Muthana, L. Su, L. X. Wang, ACS Chem. Biol. 2022, 17, 3013–3023.
10.1021/acschembio.1c00751
CAS PubMed Web of Science® Google Scholar
8
8aG. Ahn, S. M. Banik, C. L. Miller, N. M. Riley, J. R. Cochran, C. R. Bertozzi, Nat. Chem. Biol. 2021, 17, 937–946;
10.1038/s41589-021-00770-1
CAS PubMed Web of Science® Google Scholar
8bD. F. Caianiello, M. Zhang, J. D. Ray, R. A. Howell, J. C. Swartzel, E. M. J. Branham, E. Chirkin, V. R. Sabbasani, A. Z. Gong, D. M. McDonald, V. Muthusamy, D. A. Spiegel, Nat. Chem. Biol. 2021, 17, 947–953;
10.1038/s41589-021-00851-1
CAS PubMed Web of Science® Google Scholar
8cY. Zhou, P. Teng, N. T. Montgomery, X. Li, W. Tang, ACS Cent. Sci. 2021, 7, 499–506.
10.1021/acscentsci.1c00146
CAS PubMed Web of Science® Google Scholar
9J. Zheng, W. He, J. Li, X. Feng, Y. Li, B. Cheng, Y. Zhou, M. Li, K. Liu, X. Shao, J. Zhang, H. Li, L. Chen, L. Fang, J. Am. Chem. Soc. 2022, 144, 21831–21836.
10.1021/jacs.2c08367
CAS PubMed Web of Science® Google Scholar
10J. Paulk, Nat. Chem. Biol. 2021, 17, 931–933.
10.1038/s41589-021-00835-1
CAS PubMed Web of Science® Google Scholar
11
11aA. Saminathan, M. Zajac, P. Anees, Y. Krishnan, Nat. Rev. Mater. 2022, 7, 355–371;
10.1038/s41578-021-00396-8
Web of Science® Google Scholar
11bA. Lacroix, H. F. Sleiman, ACS Nano 2021, 15, 3631–3645;
10.1021/acsnano.0c06136
CAS PubMed Web of Science® Google Scholar
11cQ. Hu, H. Li, L. Wang, H. Gu, C. Fan, Chem. Rev. 2019, 119, 6459–6506;
10.1021/acs.chemrev.7b00663
CAS PubMed Web of Science® Google Scholar
11dJ. I. Cutler, E. Auyeung, C. A. Mirkin, J. Am. Chem. Soc. 2012, 134, 1376–1391.
10.1021/ja209351u
CAS PubMed Web of Science® Google Scholar
12
12aX. Peng, S. Fang, B. Ji, M. Li, J. Song, L. Qiu, W. Tan, Nano Lett. 2021, 21, 6946–6951;
10.1021/acs.nanolett.1c02191
CAS PubMed Web of Science® Google Scholar
12bY. Wang, E. Benson, F. Fördős, M. Lolaico, I. Baars, T. Fang, A. I. Teixeira, B. Högberg, Adv. Mater. 2021, 33, 2008457;
10.1002/adma.202008457
CAS PubMed Web of Science® Google Scholar
12cS. Wang, Y. Chen, S. Wang, P. Li, C. A. Mirkin, O. K. Farha, J. Am. Chem. Soc. 2019, 141, 2215–2219;
10.1021/jacs.8b12705
CAS PubMed Web of Science® Google Scholar
12dP. Wang, M. A. Rahman, Z. Zhao, K. Weiss, C. Zhang, Z. Chen, S. J. Hurwitz, Z. G. Chen, D. M. Shin, Y. Ke, J. Am. Chem. Soc. 2018, 140, 2478–2484;
10.1021/jacs.7b09024
CAS PubMed Web of Science® Google Scholar
12eG. Vindigni, S. Raniolo, A. Ottaviani, M. Falconi, O. Franch, B. R. Knudsen, A. Desideri, S. Biocca, ACS Nano 2016, 10, 5971–5979;
10.1021/acsnano.6b01402
CAS PubMed Web of Science® Google Scholar
12fK. Ezzat, Y. Aoki, T. Koo, G. McClorey, L. Benner, A. Coenen-Stass, L. O'Donovan, T. Lehto, A. Garcia-Guerra, J. Nordin, A. F. Saleh, M. Behlke, J. Morris, A. Goyenvalle, B. Dugovic, C. Leumann, S. Gordon, M. J. Gait, S. El-Andaloussi, M. J. Wood, Nano Lett. 2015, 15, 4364–4373;
10.1021/acs.nanolett.5b00490
CAS PubMed Web of Science® Google Scholar
12gJ. Choi Chung Hang, L. Hao, P. Narayan Suguna, E. Auyeung, A. Mirkin Chad, Proc. Natl. Acad. Sci. USA 2013, 110, 7625–7630;
10.1073/pnas.1305804110
CAS PubMed Web of Science® Google Scholar
12hL. Liang, J. Li, Q. Li, Q. Huang, J. Shi, H. Yan, C. Fan, Angew. Chem. Int. Ed. 2014, 53, 7745–7750;
10.1002/anie.201403236
CAS PubMed Web of Science® Google Scholar
Angew. Chem. 2014, 126, 7879–7884.
10.1002/ange.201403236
Web of Science® Google Scholar
13
13aZ. Chen, Z. Wei, F. Xiao, Z. Chao, J. Lu, Z. Wang, L. Tian, Adv. Funct. Mater. 2022, 32, 2207845;
10.1002/adfm.202207845
CAS Web of Science® Google Scholar
13bP. Kumthekar, C. H. Ko, T. Paunesku, K. Dixit, A. M. Sonabend, O. Bloch, M. Tate, M. Schwartz, L. Zuckerman, R. Lezon, R. V. Lukas, B. Jovanovic, K. McCortney, H. Colman, S. Chen, B. Lai, O. Antipova, J. Deng, L. Li, S. Tommasini-Ghelfi, L. A. Hurley, D. Unruh, N. V. Sharma, M. Kandpal, F. M. Kouri, R. V. Davuluri, D. J. Brat, M. Muzzio, M. Glass, V. Vijayakumar, J. Heidel, F. J. Giles, A. K. Adams, C. D. James, G. E. Woloschak, C. Horbinski, A. H. Stegh, Sci. Transl. Med. 2021, 13, eabb3945;
10.1126/scitranslmed.abb3945
CAS PubMed Web of Science® Google Scholar
13cL. Chen, G. Li, X. Wang, J. Li, Y. Zhang, ACS Nano 2021, 15, 11929–11939;
10.1021/acsnano.1c03072
CAS PubMed Web of Science® Google Scholar
13dM. Zheng, T. Jiang, W. Yang, Y. Zou, H. Wu, X. Liu, F. Zhu, R. Qian, D. Ling, K. McDonald, J. Shi, B. Shi, Angew. Chem. Int. Ed. 2019, 58, 4938–4942;
10.1002/anie.201814289
CAS PubMed Web of Science® Google Scholar
Angew. Chem. 2019, 131, 4992–4996;
10.1002/ange.201814289
Web of Science® Google Scholar
13eX. Tan, X. Lu, F. Jia, X. Liu, Y. Sun, J. K. Logan, K. Zhang, J. Am. Chem. Soc. 2016, 138, 10834–10837;
10.1021/jacs.6b07554
CAS PubMed Web of Science® Google Scholar
13fJ. I. Cutler, K. Zhang, D. Zheng, E. Auyeung, A. E. Prigodich, C. A. Mirkin, J. Am. Chem. Soc. 2011, 133, 9254–9257.
10.1021/ja203375n
CAS PubMed Web of Science® Google Scholar
14K. Dan, A. T. Veetil, K. Chakraborty, Y. Krishnan, Nat. Nanotechnol. 2019, 14, 252–259.
10.1038/s41565-019-0365-6
CAS PubMed Web of Science® Google Scholar
15
15aY. Dong, C. Yao, Y. Zhu, L. Yang, D. Luo, D. Yang, Chem. Rev. 2020, 120, 9420–9481;
10.1021/acs.chemrev.0c00294
CAS PubMed Web of Science® Google Scholar
15bM. E. Distler, M. H. Teplensky, K. E. Bujold, C. D. Kusmierz, M. Evangelopoulos, C. A. Mirkin, J. Am. Chem. Soc. 2021, 143, 13513–13518;
10.1021/jacs.1c07240
CAS PubMed Web of Science® Google Scholar
15cY. Kawamoto, W. Liu, J. H. Yum, S. Park, H. Sugiyama, Y. Takahashi, Y. Takakura, ChemBioChem 2022, 23, e202100583.
10.1002/cbic.202100583
CAS PubMed Web of Science® Google Scholar
16
16aX. Wang, X. Xiao, Y. Feng, J. Li, Y. Zhang, Chem. Sci. 2022, 13, 5345–5352;
10.1039/D2SC01672A
CAS PubMed Web of Science® Google Scholar
16bX. Wang, Y. Wang, J. Li, T. Tian, J. Li, Z. Guo, Y. Zhang, Adv. Ther. 2022, 5, 2100161.
10.1002/adtp.202100161
CAS Web of Science® Google Scholar
17P. J. Gough, S. Gordon, Microbes Infect. 2000, 2, 305–311.
10.1016/S1286-4579(00)00297-5
CAS PubMed Web of Science® Google Scholar
18S. Romano, N. Fonseca, S. Simões, J. Gonçalves, J. N. Moreira, Drug Discovery Today 2019, 24, 1985–2001.
10.1016/j.drudis.2019.06.018
CAS PubMed Web of Science® Google Scholar
19M. Koutsioumpa, E. Papadimitriou, Recent Pat. Anti-Cancer Drug Discovery 2014, 9, 137–152.
10.2174/1574892808666131119095953
CAS PubMed Web of Science® Google Scholar
20P. J. Bates, D. A. Laber, D. M. Miller, S. D. Thomas, J. O. Trent, Exp. Mol. Pathol. 2009, 86, 151–164.
10.1016/j.yexmp.2009.01.004
CAS PubMed Web of Science® Google Scholar
21K. Prapainop, R. Miao, C. Åberg, A. Salvati, K. A. Dawson, Nanoscale 2017, 9, 11261–11268.
10.1039/C7NR03254D
CAS PubMed Web of Science® Google Scholar
22D. Hoja-Łukowicz, S. Kedracka-Krok, W. Duda, A. Lityńska, Cell. Mol. Biol. Lett. 2014, 19, 461–482.
10.2478/s11658-014-0206-4
CAS PubMed Web of Science® Google Scholar
23M. C. Garcia, J. Williams, K. Johnson, K. Olden, J. D. Roberts, FEBS Lett. 2011, 585, 618–622.
10.1016/j.febslet.2011.01.035
CAS PubMed Web of Science® Google Scholar
24
24aJ. Canton, D. Neculai, S. Grinstein, Nat. Rev. Immunol. 2013, 13, 621–634;
10.1038/nri3515
CAS PubMed Web of Science® Google Scholar
24bA. Alquraini, J. El Khoury, Curr. Biol. 2020, 30, R790–R795.
10.1016/j.cub.2020.05.051
CAS PubMed Web of Science® Google Scholar