Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Peptide-based PROTACs: Current Challenges and Future Perspectives

Author(s): Huidan Wang, Miao Chen, Xiaoyuan Zhang, Songbo Xie, Jie Qin* and Jingrui Li*

Volume 31, Issue 2, 2024

Published on: 20 March, 2023

Page: [208 - 222] Pages: 15

DOI: 10.2174/0929867330666230130121822

Price: $65

Open Access Journals Promotions 2
Abstract

Proteolysis-targeting chimeras (PROTACs) are an attractive means to target previously undruggable or drug-resistant mutant proteins. While small molecule-based PROTACs are stable and can cross cell membranes, there is limited availability of suitable small molecule warheads capable of recruiting proteins to an E3 ubiquitin ligase for degradation. With advances in structural biology and in silico protein structure prediction, it is now becoming easier to define highly selective peptides suitable for PROTAC design. As a result, peptide-based PROTACs are becoming a feasible proposition for targeting previously “undruggable” proteins not amenable to small molecule inhibition. In this review, we summarize recent progress in the design and application of peptide-based PROTACs as well as several practical approaches for obtaining candidate peptides for PROTACs. We also discuss the major hurdles preventing the translation of peptide-based PROTACs from bench to bedside, such as their delivery and bioavailability, with the aim of stimulating discussion about how best to accelerate the clinical development of peptide- based PROTACs in the near future.

Keywords: Peptide-based PROTAC, targeted protein degradation, drug delivery, undruggable protein, E3 ubiquitin, mutant proteins

« Previous Next »
[1]
Nakamura, Y.; Kawazoe, A.; Lordick, F.; Janjigian, Y.Y.; Shitara, K. Biomarker-targeted therapies for advanced- stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat. Rev. Clin. Oncol., 2021, 18(8), 473-487.
[http://dx.doi.org/10.1038/s41571-021-00492-2] [PMID: 33790428]
[2]
Hanzl, A.; Winter, G.E. Targeted protein degradation: current and future challenges. Curr. Opin. Chem. Biol., 2020, 56, 35-41.
[http://dx.doi.org/10.1016/j.cbpa.2019.11.012] [PMID: 31901786]
[3]
Waddell, A.R.; Liao, D. Assays for validating histone acetyltransferase inhibitors. J Vis Exp, 2020, 162, 61289.
[http://dx.doi.org/10.3791/61289]
[4]
Zhang, D.; Baek, S.H.; Ho, A.; Lee, H.; Jeong, Y.S.; Kim, K. Targeted degradation of proteins by small molecules: a novel tool for functional proteomics. Comb. Chem. High Throughput Screen., 2004, 7(7), 689-697.
[http://dx.doi.org/10.2174/1386207043328364] [PMID: 15578931]
[5]
Kashani, B.; Zandi, Z.; Kaveh, V.; Pourbagheri-Sigaroodi, A.; Ghaffari, S.H.; Bashash, D. Small molecules with huge impacts: the role of miRNA-regulated PI3K pathway in human malignancies. Mol. Biol. Rep., 2021, 48(12), 8045-8059.
[http://dx.doi.org/10.1007/s11033-021-06739-6] [PMID: 34689281]
[6]
Gonzalvez, F.; Vincent, S.; Baker, T.E.; Gould, A.E.; Li, S.; Wardwell, S.D.; Nadworny, S.; Ning, Y.; Zhang, S.; Huang, W.S.; Hu, Y.; Li, F.; Greenfield, M.T.; Zech, S.G.; Das, B.; Narasimhan, N.I.; Clackson, T.; Dalgarno, D.; Shakespeare, W.C.; Fitzgerald, M.; Chouitar, J.; Griffin, R.J.; Liu, S.; Wong, K.; Zhu, X.; Rivera, V.M. Mobocertinib (TAK-788): A targeted inhibitor of EGFR exon 20 insertion mutants in non–small cell lung cancer. Cancer Discov., 2021, 11(7), 1672-1687.
[http://dx.doi.org/10.1158/2159-8290.CD-20-1683] [PMID: 33632773]
[7]
Li, Y.; Song, J.; Zhou, P.; Zhou, J.; Xie, S. Targeting undruggable transcription factors with PROTACs: Advances and perspectives. J. Med. Chem., 2022, 65(15), 10183-10194.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00691] [PMID: 35881047]
[8]
Zeng, S.; Huang, W.; Zheng, X.; Cheng, L.; Zhang, Z.; Wang, J.; Shen, Z. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges. Eur. J. Med. Chem., 2021, 210, 112981.
[http://dx.doi.org/10.1016/j.ejmech.2020.112981] [PMID: 33160761]
[9]
Békés, M.; Langley, D.R.; Crews, C.M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov., 2022, 21(3), 181-200.
[http://dx.doi.org/10.1038/s41573-021-00371-6] [PMID: 35042991]
[10]
Yang, Z.; Sun, Y.; Ni, Z.; Yang, C.; Tong, Y.; Liu, Y.; Li, H.; Rao, Y. Merging PROTAC and molecular glue for degrading BTK and GSPT1 proteins concurrently. Cell Res., 2021, 31(12), 1315-1318.
[http://dx.doi.org/10.1038/s41422-021-00533-6] [PMID: 34417569]
[11]
Guenette, R.G.; Yang, S.W.; Min, J.; Pei, B.; Potts, P.R. Target and tissue selectivity of PROTAC degraders. Chem. Soc. Rev., 2022, 51(14), 5740-5756.
[http://dx.doi.org/10.1039/D2CS00200K] [PMID: 35587208]
[12]
Au, Y.Z.; Wang, T.; Sigua, L.H.; Qi, J. Peptide-based PROTAC: The predator of pathological proteins. Cell Chem. Biol., 2020, 27(6), 637-639.
[http://dx.doi.org/10.1016/j.chembiol.2020.06.002] [PMID: 32559499]
[13]
Morris, M.C.; Depollier, J.; Mery, J.; Heitz, F.; Divita, G. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat. Biotechnol., 2001, 19(12), 1173-1176.
[http://dx.doi.org/10.1038/nbt1201-1173] [PMID: 11731788]
[14]
Sekine, K.; Takubo, K.; Kikuchi, R.; Nishimoto, M.; Kitagawa, M.; Abe, F.; Nishikawa, K.; Tsuruo, T.; Naito, M. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J. Biol. Chem., 2008, 283(14), 8961-8968.
[http://dx.doi.org/10.1074/jbc.M709525200] [PMID: 18230607]
[15]
Rana, S.; Mallareddy, J.R.; Singh, S.; Boghean, L.; Natarajan, A. Inhibitors, PROTACs and molecular glues as diverse therapeutic modalities to target cyclin-dependent kinase. Cancers (Basel), 2021, 13(21), 5506.
[http://dx.doi.org/10.3390/cancers13215506] [PMID: 34771669]
[16]
Zhao, Y.; Shu, Y.; Lin, J.; Chen, Z.; Xie, Q.; Bao, Y.; Lu, L.; Sun, N.; Wang, Y. Discovery of novel BTK PROTACs for B-Cell lymphomas. Eur. J. Med. Chem., 2021, 225, 113820.
[http://dx.doi.org/10.1016/j.ejmech.2021.113820] [PMID: 34509879]
[17]
Wang, H.; Li, C.; Liu, X.; Ma, M. Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase. Bioorg. Med. Chem., 2022, 61, 116707.
[http://dx.doi.org/10.1016/j.bmc.2022.116707] [PMID: 35344835]
[18]
Xiang, W.; Zhao, L.; Han, X.; Qin, C.; Miao, B.; McEachern, D.; Wang, Y.; Metwally, H.; Kirchhoff, P.D.; Wang, L.; Matvekas, A.; He, M.; Wen, B.; Sun, D.; Wang, S. Discovery of ARD-2585 as an exceptionally potent and orally active PROTAC degrader of androgen receptor for the treatment of advanced prostate cancer. J. Med. Chem., 2021, 64(18), 13487-13509.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00900] [PMID: 34473519]
[19]
Duan, L.; Xu, X.; Xu, L.; Wen, C.; Ouyang, K.; Li, Z.; Liang, Y. ERα-targeting PROTAC as a chemical knockdown tool to investigate the estrogen receptor function in rat menopausal arthritis. Front. Pharmacol., 2021, 12, 764154.
[http://dx.doi.org/10.3389/fphar.2021.764154] [PMID: 34916941]
[20]
Backus, K.M.; Correia, B.E.; Lum, K.M.; Forli, S.; Horning, B.D.; González-Páez, G.E.; Chatterjee, S.; Lanning, B.R.; Teijaro, J.R.; Olson, A.J.; Wolan, D.W.; Cravatt, B.F. Proteome-wide covalent ligand discovery in native biological systems. Nature, 2016, 534(7608), 570-574.
[http://dx.doi.org/10.1038/nature18002] [PMID: 27309814]
[21]
Lee, K.Y.; Chau, C.H.; Price, D.K.; Figg, W.D. Drugging the undruggable: activity-based protein profiling offers opportunities for targeting the KLK activome. Cancer Biol. Ther., 2022, 23(1), 136-138.
[http://dx.doi.org/10.1080/15384047.2022.2033059] [PMID: 35129066]
[22]
Jiang, Y.; Deng, Q.; Zhao, H.; Xie, M.; Chen, L.; Yin, F.; Qin, X.; Zheng, W.; Zhao, Y.; Li, Z. Development of stabilized peptide-based PROTACs against estrogen receptor α. ACS Chem. Biol., 2018, 13(3), 628-635.
[http://dx.doi.org/10.1021/acschembio.7b00985] [PMID: 29271628]
[23]
Pelay-Gimeno, M.; Glas, A.; Koch, O.; Grossmann, T.N. Structure-based design of inhibitors of protein-protein interactions: Mimicking peptide binding epitopes. Angew. Chem. Int. Ed., 2015, 54(31), 8896-8927.
[http://dx.doi.org/10.1002/anie.201412070] [PMID: 26119925]
[24]
Ledsgaard, L.; Ljungars, A.; Rimbault, C.; Sørensen, C.V.; Tulika, T.; Wade, J.; Wouters, Y.; McCafferty, J.; Laustsen, A.H. Advances in antibody phage display technology. Drug Discov. Today, 2022, 27(8), 2151-2169.
[http://dx.doi.org/10.1016/j.drudis.2022.05.002] [PMID: 35550436]
[25]
Jaroszewicz, W.; Morcinek-Orłowska, J.; Pierzynowska, K.; Gaffke, L.; Węgrzyn, G. Phage display and other peptide display technologies. FEMS Microbiol. Rev., 2022, 46(2), fuab052.
[http://dx.doi.org/10.1093/femsre/fuab052] [PMID: 34673942]
[26]
Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA, 2001, 98(15), 8554-8559.
[http://dx.doi.org/10.1073/pnas.141230798] [PMID: 11438690]
[27]
Sakamoto, K.M.; Kim, K.B.; Verma, R.; Ransick, A.; Stein, B.; Crews, C.M.; Deshaies, R.J. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics, 2003, 2(12), 1350-1358.
[http://dx.doi.org/10.1074/mcp.T300009-MCP200] [PMID: 14525958]
[28]
Schneekloth, J.S., Jr; Fonseca, F.N.; Koldobskiy, M.; Mandal, A.; Deshaies, R.; Sakamoto, K.; Crews, C.M. Chemical genetic control of protein levels: selective in vivo targeted degradation. J. Am. Chem. Soc., 2004, 126(12), 3748-3754.
[http://dx.doi.org/10.1021/ja039025z] [PMID: 15038727]
[29]
Poongavanam, V.; Kihlberg, J. PROTAC cell permeability and oral bioavailability: a journey into uncharted territory. Future Med. Chem., 2022, 14(3), 123-126.
[http://dx.doi.org/10.4155/fmc-2021-0208] [PMID: 34583518]
[30]
Klein, V.G.; Townsend, C.E.; Testa, A.; Zengerle, M.; Maniaci, C.; Hughes, S.J.; Chan, K.H.; Ciulli, A.; Lokey, R.S. Understanding and improving the membrane permeability of VH032-based PROTACs. ACS Med. Chem. Lett., 2020, 11(9), 1732-1738.
[http://dx.doi.org/10.1021/acsmedchemlett.0c00265] [PMID: 32939229]
[31]
McAndrews, K.M.; Xiao, F.; Chronopoulos, A.; LeBleu, V.S.; Kugeratski, F.G.; Kalluri, R. Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic KrasG12D in pancreatic cancer. Life Sci. Alliance, 2021, 4(9), e202000875.
[http://dx.doi.org/10.26508/lsa.202000875] [PMID: 34282051]
[32]
Balantič, K.; Miklavčič, D.; Križaj, I.; Kramar, P. The good and the bad of cell membrane electroporation. Acta Chim. Slov., 2021, 68(4), 753-764.
[http://dx.doi.org/10.17344/acsi.2021.7198] [PMID: 34918751]
[33]
Chen, Z.; Ling, L.; Shi, X.; Li, W.; Zhai, H.; Kang, Z.; Zheng, B.; Zhu, J.; Ye, S.; Wang, H.; Tong, L.; Ni, J.; Huang, C.; Li, Y.; Zheng, K. Microinjection of antisense oligonucleotides into living mouse testis enables lncRNA function study. Cell Biosci., 2021, 11(1), 213.
[http://dx.doi.org/10.1186/s13578-021-00717-y] [PMID: 34920761]
[34]
Wender, P.A.; Mitchell, D.J.; Pattabiraman, K.; Pelkey, E.T.; Steinman, L.; Rothbard, J.B. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters. Proc. Natl. Acad. Sci. USA, 2000, 97(24), 13003-13008.
[http://dx.doi.org/10.1073/pnas.97.24.13003] [PMID: 11087855]
[35]
Kirschberg, T.A.; VanDeusen, C.L.; Rothbard, J.B.; Yang, M.; Wender, P.A. Arginine-based molecular transporters: the synthesis and chemical evaluation of releasable taxol-transporter conjugates. Org. Lett., 2003, 5(19), 3459-3462.
[http://dx.doi.org/10.1021/ol035234c] [PMID: 12967299]
[36]
Zhang, D.; Baek, S.H.; Ho, A.; Kim, K. Degradation of target protein in living cells by small-molecule proteolysis inducer. Bioorg. Med. Chem. Lett., 2004, 14(3), 645-648.
[http://dx.doi.org/10.1016/j.bmcl.2003.11.042] [PMID: 14741260]
[37]
Lee, H.; Puppala, D.; Choi, E.Y.; Swanson, H.; Kim, K.B. Targeted degradation of the aryl hydrocarbon receptor by the PROTAC approach: a useful chemical genetic tool. ChemBioChem, 2007, 8(17), 2058-2062.
[http://dx.doi.org/10.1002/cbic.200700438] [PMID: 17907127]
[38]
Bargagna-Mohan, P.; Baek, S.H.; Lee, H.; Kim, K.; Mohan, R. Use of PROTACS as molecular probes of angiogenesis. Bioorg. Med. Chem. Lett., 2005, 15(11), 2724-2727.
[http://dx.doi.org/10.1016/j.bmcl.2005.04.008] [PMID: 15876533]
[39]
Rodriguez-Gonzalez, A.; Cyrus, K.; Salcius, M.; Kim, K.; Crews, C.M.; Deshaies, R.J.; Sakamoto, K.M. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene, 2008, 27(57), 7201-7211.
[http://dx.doi.org/10.1038/onc.2008.320] [PMID: 18794799]
[40]
Montrose, K.; Krissansen, G.W. Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus. Biochem. Biophys. Res. Commun., 2014, 453(4), 735-740.
[http://dx.doi.org/10.1016/j.bbrc.2014.10.006] [PMID: 25305486]
[41]
Henning, R.K.; Varghese, J.O.; Das, S.; Nag, A.; Tang, G.; Tang, K.; Sutherland, A.M.; Heath, J.R. Degradation of Akt using protein-catalyzed capture agents. J. Pept. Sci., 2016, 22(4), 196-200.
[http://dx.doi.org/10.1002/psc.2858] [PMID: 26880702]
[42]
Wang, X.; Feng, S.; Fan, J.; Li, X.; Wen, Q.; Luo, N. New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation. Biochem. Pharmacol., 2016, 116, 200-209.
[http://dx.doi.org/10.1016/j.bcp.2016.07.017] [PMID: 27473774]
[43]
Chu, T.T.; Gao, N.; Li, Q.Q.; Chen, P.G.; Yang, X.F.; Chen, Y.X.; Zhao, Y.F.; Li, Y.M. Specific knockdown of endogenous tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem. Biol., 2016, 23(4), 453-461.
[http://dx.doi.org/10.1016/j.chembiol.2016.02.016] [PMID: 27105281]
[44]
Hines, J.; Gough, J.D.; Corson, T.W.; Crews, C.M. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc. Natl. Acad. Sci. USA, 2013, 110(22), 8942-8947.
[http://dx.doi.org/10.1073/pnas.1217206110] [PMID: 23674677]
[45]
Bauer, P.O.; Goswami, A.; Wong, H.K.; Okuno, M.; Kurosawa, M.; Yamada, M.; Miyazaki, H.; Matsumoto, G.; Kino, Y.; Nagai, Y.; Nukina, N. Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. Nat. Biotechnol., 2010, 28(3), 256-263.
[http://dx.doi.org/10.1038/nbt.1608] [PMID: 20190739]
[46]
Lu, M.; Liu, T.; Jiao, Q.; Ji, J.; Tao, M.; Liu, Y.; You, Q.; Jiang, Z. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur. J. Med. Chem., 2018, 146, 251-259.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.063] [PMID: 29407955]
[47]
Zou, Y.; Ma, D.; Wang, Y. The PROTAC technology in drug development. Cell Biochem. Funct., 2019, 37(1), 21-30.
[http://dx.doi.org/10.1002/cbf.3369] [PMID: 30604499]
[48]
Zheng, J.; Tan, C.; Xue, P.; Cao, J.; Liu, F.; Tan, Y.; Jiang, Y. Proteolysis targeting peptide (PROTAP) strategy for protein ubiquitination and degradation. Biochem. Biophys. Res. Commun., 2016, 470(4), 936-940.
[http://dx.doi.org/10.1016/j.bbrc.2016.01.158] [PMID: 26826379]
[49]
Paiva, S.L.; Crews, C.M. Targeted protein degradation: elements of PROTAC design. Curr. Opin. Chem. Biol., 2019, 50, 111-119.
[http://dx.doi.org/10.1016/j.cbpa.2019.02.022] [PMID: 31004963]
[50]
Liao, H.; Li, X.; Zhao, L.; Wang, Y.; Wang, X.; Wu, Y.; Zhou, X.; Fu, W.; Liu, L.; Hu, H.G.; Chen, Y.G. A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer. Cell Discov., 2020, 6(1), 35.
[http://dx.doi.org/10.1038/s41421-020-0171-1] [PMID: 32550000]
[51]
Tanaka, Y.; Luo, Y.; O’Shea, J.J.; Nakayamada, S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat. Rev. Rheumatol., 2022, 18(3), 133-145.
[http://dx.doi.org/10.1038/s41584-021-00726-8] [PMID: 34987201]
[52]
Alsfouk, A. Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy. J. Enzyme Inhib. Med. Chem., 2021, 36(1), 693-706.
[http://dx.doi.org/10.1080/14756366.2021.1890726] [PMID: 33632038]
[53]
Crews, C.M. Inducing protein degradation as a therapeutic strategy. J. Med. Chem., 2018, 61(2), 403-404.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01333] [PMID: 29164885]
[54]
Crews, C.M.; Georg, G.; Wang, S. Inducing protein degradation as a therapeutic strategy. J. Med. Chem., 2016, 59(11), 5129-5130.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00735] [PMID: 27199030]
[55]
Cao, L.; Coventry, B.; Goreshnik, I.; Huang, B.; Sheffler, W.; Park, J.S.; Jude, K.M.; Marković, I.; Kadam, R.U.; Verschueren, K.H.G.; Verstraete, K.; Walsh, S.T.R.; Bennett, N.; Phal, A.; Yang, A.; Kozodoy, L.; DeWitt, M.; Picton, L.; Miller, L.; Strauch, E.M.; DeBouver, N.D.; Pires, A.; Bera, A.K.; Halabiya, S.; Hammerson, B.; Yang, W.; Bernard, S.; Stewart, L.; Wilson, I.A.; Ruohola-Baker, H.; Schlessinger, J.; Lee, S.; Savvides, S.N.; Garcia, K.C.; Baker, D. Design of protein-binding proteins from the target structure alone. Nature, 2022, 605(7910), 551-560.
[http://dx.doi.org/10.1038/s41586-022-04654-9] [PMID: 35332283]
[56]
Linkous, R.O.; Sestok, A.E.; Smith, A.T. The crystal structure of Klebsiella pneumoniae FeoA reveals a site for protein-protein interactions. Proteins, 2019, 87(11), 897-903.
[http://dx.doi.org/10.1002/prot.25755] [PMID: 31162843]
[57]
Zhang, Y.; Zhong, Z.; Ye, J.; Wang, C. Crystal structure of the PDZ4 domain of MAGI2 in complex with PBM of ARMS reveals a canonical PDZ recognition mode. Neurochem. Int., 2021, 149, 105152.
[http://dx.doi.org/10.1016/j.neuint.2021.105152] [PMID: 34371146]
[58]
Nowak, R.P.; DeAngelo, S.L.; Buckley, D.; He, Z.; Donovan, K.A.; An, J.; Safaee, N.; Jedrychowski, M.P.; Ponthier, C.M.; Ishoey, M.; Zhang, T.; Mancias, J.D.; Gray, N.S.; Bradner, J.E.; Fischer, E.S. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol., 2018, 14(7), 706-714.
[http://dx.doi.org/10.1038/s41589-018-0055-y] [PMID: 29892083]
[59]
Jakhmola, S.; Sk, M.F.; Chatterjee, A.; Jain, K.; Kar, P.; Jha, H.C. A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes. Comput. Biol. Med., 2022, 148, 105856.
[http://dx.doi.org/10.1016/j.compbiomed.2022.105856] [PMID: 35863244]
[60]
Das, L.; Shekhar, S.; Chandrani, P.; Varma, A.K. In silico structural analysis of secretory clusterin to assess pathogenicity of mutations identified in the evolutionarily conserved regions. J. Biomol. Struct. Dyn., 2021, 2007791.
[http://dx.doi.org/10.1080/07391102.2021.2007791] [PMID: 34821197]
[61]
Choi, J.; Park, T.; Yul Lee, S.; Yang, J.; Seok, C. GalaxyDomDock: An ab initio domain–domain docking web server for multi-domain protein structure prediction. J. Mol. Biol., 2022, 434(11), 167508.
[http://dx.doi.org/10.1016/j.jmb.2022.167508] [PMID: 35662464]
[62]
Kootery, K.P.; Sarojini, S. Structural and functional characterization of a hypothetical protein in the RD7 region in clinical isolates of Mycobacterium tuberculosis — an in silico approach to candidate vaccines. J. Genet. Eng. Biotechnol., 2022, 20(1), 55.
[http://dx.doi.org/10.1186/s43141-022-00340-5] [PMID: 35394551]
[63]
Varadi, M.; Anyango, S.; Deshpande, M.; Nair, S.; Natassia, C.; Yordanova, G.; Yuan, D.; Stroe, O.; Wood, G.; Laydon, A.; Žídek, A.; Green, T.; Tunyasuvunakool, K.; Petersen, S.; Jumper, J.; Clancy, E.; Green, R.; Vora, A.; Lutfi, M.; Figurnov, M.; Cowie, A.; Hobbs, N.; Kohli, P.; Kleywegt, G.; Birney, E.; Hassabis, D.; Velankar, S. AlphaFold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res., 2022, 50(D1), D439-D444.
[http://dx.doi.org/10.1093/nar/gkab1061] [PMID: 34791371]
[64]
David, A.; Islam, S.; Tankhilevich, E.; Sternberg, M.J.E. The alphaFold database of protein structures: A biologist’s guide. J. Mol. Biol., 2022, 434(2), 167336.
[http://dx.doi.org/10.1016/j.jmb.2021.167336] [PMID: 34757056]
[65]
Bagdonas, H.; Fogarty, C.A.; Fadda, E.; Agirre, J. The case for post-predictional modifications in the alphaFold protein structure database. Nat. Struct. Mol. Biol., 2021, 28(11), 869-870.
[http://dx.doi.org/10.1038/s41594-021-00680-9] [PMID: 34716446]
[66]
Wheeler, R.J. A resource for improved predictions of Trypanosoma and Leishmania protein three-dimensional structure. PLoS One, 2021, 16(11), e0259871.
[http://dx.doi.org/10.1371/journal.pone.0259871] [PMID: 34762696]
[67]
Pla-Prats, C.; Thomä, N.H. Quality control of protein complex assembly by the ubiquitin–proteasome system. Trends Cell Biol., 2022, 32(8), 696-706.
[http://dx.doi.org/10.1016/j.tcb.2022.02.005] [PMID: 35300891]
[68]
Ottis, P.; Toure, M.; Cromm, P.M.; Ko, E.; Gustafson, J.L.; Crews, C.M. Assessing different E3 ligases for small molecule induced protein ubiquitination and degradation. ACS Chem. Biol., 2017, 12(10), 2570-2578.
[http://dx.doi.org/10.1021/acschembio.7b00485] [PMID: 28767222]
[69]
Qu, J.; Ren, X.; Xue, F.; He, Y.; Zhang, R.; Zheng, Y.; Huang, H.; Wang, W.; Zhang, J. Specific knockdown of α-synuclein by peptide-directed proteasome degradation rescued its associated neurotoxicity. Cell Chem. Biol., 2020, 27(6), 751-762.e4.
[http://dx.doi.org/10.1016/j.chembiol.2020.03.010] [PMID: 32359427]
[70]
An, S.; Fu, L. Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs. EBioMedicine, 2018, 36, 553-562.
[http://dx.doi.org/10.1016/j.ebiom.2018.09.005] [PMID: 30224312]
[71]
Arvinas, Pfizer team up on PROTACs. Cancer Discov., 2018, 8(4), 377-378.
[http://dx.doi.org/10.1158/2159-8290.CD-NB2018-015] [PMID: 29453240]
[72]
Itoh, Y. Chemical protein degradation approach and its application to epigenetic targets. Chem. Rec., 2018, 18(12), 1681-1700.
[http://dx.doi.org/10.1002/tcr.201800032] [PMID: 29893461]
[73]
Yang, Y.; Yang, Y.; Xie, X.; Cai, X.; Mei, X. Preparation and characterization of photo-responsive cell-penetrating peptide-mediated nanostructured lipid carrier. J. Drug Target., 2014, 22(10), 891-900.
[http://dx.doi.org/10.3109/1061186X.2014.940589] [PMID: 25045925]
[74]
Visca, H.; DuPont, M.; Moshnikova, A.; Crawford, T.; Engelman, D.M.; Andreev, O.A.; Reshetnyak, Y.K. pHLIP peptides target acidity in activated macrophages. Mol. Imaging Biol., 2022, 24(6), 874-885.
[http://dx.doi.org/10.1007/s11307-022-01737-x] [PMID: 35604527]
[75]
Sun, Y.; Hu, L.; Yang, P.; Zhang, M.; Wang, X.; Xiao, H.; Qiao, C.; Wang, J.; Luo, L.; Feng, J.; Zheng, Y.; Wang, Y.; Shi, Y.; Chen, G. H low insertion peptide-modified programmed cell death-ligand 1 potently suppresses T-Cell activation under acidic condition. Front. Immunol., 2021, 12, 794226.
[http://dx.doi.org/10.3389/fimmu.2021.794226] [PMID: 35003115]
[76]
Otieno, S.A.; Qiang, W. Roles of key residues and lipid dynamics reveal pHLIP-membrane interactions at intermediate pH. Biophys. J., 2021, 120(21), 4649-4662.
[http://dx.doi.org/10.1016/j.bpj.2021.10.001] [PMID: 34624273]
[77]
Andreev, O.A.; Engelman, D.M.; Reshetnyak, Y.K. pH-sensitive membrane peptides (pHLIPs) as a novel class of delivery agents. Mol. Membr. Biol., 2010, 27(7), 341-352.
[http://dx.doi.org/10.3109/09687688.2010.509285] [PMID: 20939768]
[78]
a) Gao, X.; Ran, N.; Dong, X.; Zuo, B.; Yang, R.; Zhou, Q.; Moulton, H.M.; Seow, Y.; Yin, H. Anchor peptide captures, targets, and loads exosomes of diverse origins for diagnostics and therapy. Sci. Transl. Med., 2018, 10(444), eaat0195.
[http://dx.doi.org/10.1126/scitranslmed.aat0195] [PMID: 29875202];
b) Dong, X.; Lei, Y.; Yu, Z.; Wang, T.; Liu, Y.; Han, G.; Zhang, X.; Li, Y.; Song, Y.; Xu, H.; Du, M.; Yin, H.; Wang, X.; Yan, H. Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis. Theranostics, 2021, 11, 5107-5126.
[79]
Okuda, A.; Futaki, S. Protein delivery to cytosol by cell-penetrating peptide bearing tandem repeat penetration-accelerating sequence. Methods Mol. Biol., 2022, 2383, 265-273.
[http://dx.doi.org/10.1007/978-1-0716-1752-6_18] [PMID: 34766296]
[80]
Yang, Q.; Tang, J.; Xu, C.; Zhao, H.; Zhou, Y.; Wang, Y.; Yang, M.; Chen, X.; Chen, J. Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation. J. Mol. Cell Biol., 2021, 12(12), 933-945.
[http://dx.doi.org/10.1093/jmcb/mjaa043] [PMID: 32770227]
[81]
Nguyen, H.C.; Yang, H.; Fribourgh, J.L.; Wolfe, L.S.; Xiong, Y. Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex. Structure, 2015, 23(3), 441-449.
[http://dx.doi.org/10.1016/j.str.2014.12.014] [PMID: 25661653]
[82]
Zengerle, M.; Chan, K.H.; Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol., 2015, 10(8), 1770-1777.
[http://dx.doi.org/10.1021/acschembio.5b00216] [PMID: 26035625]
[83]
Lebraud, H.; Wright, D.J.; Johnson, C.N.; Heightman, T.D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent. Sci., 2016, 2(12), 927-934.
[http://dx.doi.org/10.1021/acscentsci.6b00280] [PMID: 28058282]
[84]
Wurz, R.P.; Dellamaggiore, K.; Dou, H.; Javier, N.; Lo, M.C.; McCarter, J.D.; Mohl, D.; Sastri, C.; Lipford, J.R.; Cee, V.J. “Click Chemistry Platform” for the rapid synthesis of bispecific molecules for inducing protein degradation. J. Med. Chem., 2018, 61(2), 453-461.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01781] [PMID: 28378579]
[85]
Rong, G. Fluoroalkylation promotes cytosolic peptide delivery. Sci Adv, 2020, 6(33), eaaz1774.
[http://dx.doi.org/10.1126/sciadv.aaz1774]
[86]
Rueping, M.; Mahajan, Y.; Sauer, M.; Seebach, D. Cellular uptake studies with beta-peptides. ChemBioChem, 2002, 3(2-3), 257-259.
[http://dx.doi.org/10.1002/1439-7633(20020301)3:2/3<257::AID-CBIC257>3.0.CO;2-S] [PMID: 11921409]
[87]
Valeur, E.; Guéret, S.M.; Adihou, H.; Gopalakrishnan, R.; Lemurell, M.; Waldmann, H.; Grossmann, T.N.; Plowright, A.T. New modalities for challenging targets in drug discovery. Angew. Chem. Int. Ed., 2017, 56(35), 10294-10323.
[http://dx.doi.org/10.1002/anie.201611914] [PMID: 28186380]
[88]
Fuller, J.C.; Burgoyne, N.J.; Jackson, R.M. Predicting druggable binding sites at the protein–protein interface. Drug Discov. Today, 2009, 14(3-4), 155-161.
[http://dx.doi.org/10.1016/j.drudis.2008.10.009] [PMID: 19041415]
[89]
Schneider, M.; Radoux, C.J.; Hercules, A.; Ochoa, D.; Dunham, I.; Zalmas, L.P.; Hessler, G.; Ruf, S.; Shanmugasundaram, V.; Hann, M.M.; Thomas, P.J.; Queisser, M.A.; Benowitz, A.B.; Brown, K.; Leach, A.R. The PROTACtable genome. Nat. Rev. Drug Discov., 2021, 20(10), 789-797.
[http://dx.doi.org/10.1038/s41573-021-00245-x] [PMID: 34285415]
[90]
Cromm, P.M.; Crews, C.M. Targeted protein degradation: from chemical biology to drug discovery. Cell Chem. Biol., 2017, 24(9), 1181-1190.
[http://dx.doi.org/10.1016/j.chembiol.2017.05.024] [PMID: 28648379]

Rights & Permissions Print Cite
Article Metrics
145
1
Wayfinder Image
Open Access Journals Promotions
World Antimicrobial Awareness Week
© 2024 Bentham Science Publishers | Privacy Policy