Review
Pharmacology & Pharmacy
Si-Min Qi, Jinyun Dong, Zhi-Yuan Xu, Xiang-Dong Cheng, Wei-Dong Zhang, Jiang-Jiang Qin
Summary: PROTAC technology is an effective method for degrading target proteins through the ubiquitin-proteasome system, with promising applications in cancer treatment. The first oral PROTACs have shown encouraging results in clinical trials, sparking greater enthusiasm for PROTAC research.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Oncology
Moyang Lv, Weichao Hu, Shengwei Zhang, Lijiao He, Changjiang Hu
Summary: Proteolysis-targeting chimeras (PROTACs) are a promising class of drugs that can effectively target undruggable proteins and have potential applications in cancer therapy. This review provides an overview of PROTAC technology and highlights recent clinical trials, as well as novel findings and strategies to enhance PROTAC antitumor activity.
Review
Cell Biology
Yosup Kim, Eun-Kyung Kim, Yoona Chey, Min-Jeong Song, Ho Hee Jang
Summary: The proteasome is a multi-catalytic protease complex that regulates protein quality control. It selectively degrades cellular proteins through ubiquitination and plays a critical role in maintaining protein homeostasis. This article summarizes the proteasome's structure, regulatory mechanisms, proteins that control its activity, and its involvement in various diseases, chemoresistant cells, and cancer stem cells. Potential therapeutic modalities that target the ubiquitin-proteasome system are also discussed.
Review
Biochemistry & Molecular Biology
Na Yang, Bo Kong, Zhaohong Zhu, Fei Huang, Liliang Zhang, Tao Lu, Yadong Chen, Yanmin Zhang, Yulei Jiang
Summary: Targeted protein degradation (TPD) technology, such as PROTACs, has become widespread in the past 20 years and greatly accelerates the development of disease treatment. Unlike small inhibitors, targeted protein degraders can target undruggable targets and overcome drug resistance through ubiquitin-proteasome pathway (UPP) and lysosome pathway. This review discusses different degradation technologies and provides a basis for future research.
MOLECULAR DIVERSITY
(2023)
Review
Cell Biology
Ming He, Wenxing Lv, Yu Rao
Summary: PROTAC is a new technology for inducing protein degradation using small molecules, which shows advantages in overcoming tumor resistance, affecting non-enzymatic functions of target proteins, degrading undruggable targets, and providing rapid and reversible chemical knockout tools. However, it also faces challenges and issues as a rapidly developing new chemical biology technology.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Bayonle Aminu, Julia Fux, Evan Mallette, Nathaniel Petersen, Wei Zhang
Summary: The Ubiquitin Variant Induced Proximity (UbVIP) technology allows for targeted degradation of proteins, showing potential as a therapeutic approach for human diseases. By utilizing synthetic UbV binders and designing multi-domain fusion proteins, researchers were able to induce proteasomal degradation of a nucleus-localized protein 53BP1. This study demonstrates the suitability of UbV technology for developing protein-based molecules for targeted degradation and identifying novel E3 ligases.
Article
Cell Biology
Martin P. Schwalm, Lena M. Berger, Maximilian N. Meuter, James D. Vasta, Cesear R. Corona, Sandra Roehm, Benedict-Tilman Berger, Frederic Farges, Sebastian M. Beinert, Franziska Preuss, Viktoria Morasch, Vladimir V. Rogov, Sebastian Mathea, Krishna Saxena, Matthew B. Robers, Susanne Mueller, Stefan Knapp
Summary: E3 ligases play a crucial role in regulating protein homeostasis by recruiting substrate proteins to the proteasomal degradation machinery. Recent research has focused on the Baculovirus IAP Repeat (BIR) family of E3 ligases, which contain a structurally conserved but diverse protein interaction domain. The Inhibitors of Apoptosis (IAP) family, which typically have three BIR domains, are promising drug targets. However, there is currently a lack of assay tools to evaluate the selectivity of inhibitors in this target area.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yong Chen, Xue Yuan, Minghai Tang, Mingsong Shi, Tao Yang, Kongjun Liu, Dexin Deng, Lijuan Chen
Summary: The discovery of small molecule FLT3 degraders based on PROTAC, such as the promising PF15, has shown significant inhibition of FLT3-ITD-positive cell proliferation, induced FLT3 degradation, and down-regulated FLT3 and STAT5 phosphorylation levels, laying a strong foundation for the potential use of FLT3-PROTAC molecules as an effective strategy for treating AML.
BIOORGANIC CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Jaeseok Lee, Youngjun Lee, Young Mee Jung, Ju Hyun Park, Hyuk Sang Yoo, Jongmin Park
Summary: Target protein degradation is an emerging strategy for therapeutics discovery. Proteolysis-targeting chimera (PROTAC) utilizes cellular ubiquitin-dependent proteolysis system to efficiently degrade a protein of interest. However, the current PROTAC technology is limited by the cell type specific expression of E3 ligases and resistance to CRBN or VHL ligands. Therefore, the discovery of new E3 ligase ligands is crucial for improving PROTAC technology.
Review
Pharmacology & Pharmacy
Marcin Cieslak, Marta Slowianek
Summary: The traditional low-molecular-weight drugs target specific biological targets with receptor or enzymatic activity to inhibit their function. However, there are disease proteins that cannot be targeted using this approach. PROTACs, on the other hand, can bind both the protein of interest and the E3 ubiquitin ligase complex, leading to degradation. This review focuses on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis.
Review
Biochemistry & Molecular Biology
Marta Pichlak, Tomasz Sobierajski, Katarzyna M. Blazewska, Edyta Gendaszewska-Darmach
Summary: PROTACs are a promising field in medicinal chemistry, with compounds that have reached clinical studies. They target posttranslational modifications and have shown significant progress in targeting kinases. This study focuses on a less popular class of PROTACs that target enzymes involved in lysine acetylation/deacetylation, lysine and arginine methylation, ADP-ribosylation, E3 ligases, and ubiquitin-specific proteases. The authors emphasize the importance of understanding the structural aspects of PROTAC elements to aid in the development of these compounds.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Xinyi Li, Wenchen Pu, Qingquan Zheng, Min Ai, Song Chen, Yong Peng
Summary: PROTAC is an engineered technique for targeted protein degradation, which recruits target protein and E3 ubiquitin ligase to trigger the degradation of target protein. It has great potential in cancer therapy and offers advantages over traditional anti-cancer therapies.
Review
Biochemistry & Molecular Biology
Carolyn Allain Breckel, Mark Hochstrasser
Summary: The proper folding of proteins is vital for their diverse functions, and misfolded proteins can potentially harm cells by forming aggregates. Protein quality control pathways are responsible for repairing or degrading abnormal proteins, with the ubiquitin-proteasome system being commonly employed.
Review
Biochemistry & Molecular Biology
David C. Hughes, Leslie M. Baehr, David S. Waddell, Adam P. Sharples, Sue C. Bodine
Summary: The development and prevalence of diseases associated with aging have a global health burden on society. One hallmark of aging is the loss of proteostasis, partly caused by alterations to the ubiquitin-proteasome system and lysosome-autophagy system, leading to impaired function and maintenance of mass in tissues such as skeletal muscle. In skeletal muscle, functional impairment occurs early in the aging process and depends on proteostatic mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Tommaso Palomba, Massimo Baroni, Simon Cross, Gabriele Cruciani, Lydia Siragusa
Summary: Proteolysis-targeting chimeras (PROTACs) are novel therapeutics that utilize E3 ligases to degrade target proteins. Existing databases on E3 ligases have limited information on their structures and ligands. This study presents an accurate and comprehensive platform, ELIOT, to navigate and select new E3 ligases and ligands for the design of new PROTACs.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Editorial Material
Biochemistry & Molecular Biology
Waka Sato, Mikihiko Naito
Article
Biochemistry & Molecular Biology
Yoshino Akizuki, Mai Morita, Yuki Mori, Ai Kaiho-Soma, Shivani Dixit, Akinori Endo, Marie Shimogawa, Gosuke Hayashi, Mikihiko Naito, Akimitsu Okamoto, Keiji Tanaka, Yasushi Saeki, Fumiaki Ohtake
Summary: Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is a new concept in precision medicine. This study reveals the importance of K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrates the diversity of the ubiquitin code used for chemical hijacking.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Infectious Diseases
Mayu Takada, Takahito Ito, Megumi Kurashima, Natsumi Matsunaga, Yosuke Demizu, Takashi Misawa
Summary: Antimicrobial peptides (AMPs) have shown promise as next-generation drugs for infectious diseases. The development of a novel antimicrobial peptide, 17KKV, based on the Magainin 2 sequence, has demonstrated increased amphipathicity and enhanced antimicrobial activity through the introduction of non-proteinogenic amino acids and side-chain stapling. Peptide 1, containing 2-aminobutyric acid residues in the 17KKV sequence, exhibited potent antimicrobial activity against multidrug-resistant Pseudomonus aeruginosa without significant hemolytic activity.
Article
Biochemistry & Molecular Biology
Hanqiao Xu, Takashi Kurohara, Nobumichi Ohoka, Genichiro Tsuji, Takao Inoue, Mikihiko Naito, Yosuke Demizu
Summary: In this study, a solid-phase synthesis method is developed for diverse PROTAC design, which includes investigating a wider range of E3 ligands and linker structures. The study expanded the E3 ligand range to include VHL and IAP ligands, and compared the suitability of PEG and alkyl linker for PROTAC synthesis. The solid-phase synthesis methods enabled rapid synthesis of multiple PROTACs for BRD4 targeting.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Haruna Tsujimura, Miyako Naganuma, Nobumichi Ohoka, Takao Inoue, Mikihiko Naito, Genichiro Tsuji, Yosuke Demizu
Summary: Targeted protein degradation (TPD) using chimeric molecules like proteolysis-targeting chimeras (PROTACs) has been studied as a strategy to selectively degrade intracellular proteins by utilizing the ubiquitin-proteasome system (UPS). Nucleic acid aptamers have shown potential as ligands for targeting proteins for degradation. In this study, nucleic acid aptamers were linked to estrogen receptor alpha (ER alpha) and E3 ubiquitin ligase ligands to construct chimeric molecules that could degrade ER alpha via UPS. These findings demonstrate the development of novel aptamer-based PROTACs for targeting intracellular proteins.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Pharmacology & Pharmacy
Po-Chang Shih, Miyako Naganuma, Yosuke Demizu, Mikihiko Naito
Summary: Transcription factors (TFs) and RNA-binding proteins (RBPs) have been challenging to target with drugs due to their lack of ligand-binding sites and flat, narrow protein surfaces. However, protein-specific oligonucleotides have shown promise as a means to target TFs and RBPs, and the emerging PROTAC technology utilizes these oligonucleotides as warheads. This review article discusses the current state and future development of oligonucleotide-based protein degraders that rely on the ubiquitin-proteasome system or proteases.
Article
Biochemical Research Methods
Miyako Naganuma, Nobumichi Ohoka, Genichiro Tsuji, Takao Inoue, Mikihiko Naito, Yosuke Demizu
Summary: Proteolysis-targeting chimeras (PROTACs) have been developed as a chemical method to degrade proteins via the ubiquitin-proteasome system. In this study, we developed PROTACs containing chemically modified decoy oligonucleotides to improve intracellular stability and activity. Among the newly designed PROTACs, LCL-ER(dec)-H46 showed long-term degradation activity and enzyme tolerance.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Po-Chang Shih, Miyako Naganuma, Genichiro Tsuji, Yosuke Demizu, Mikihiko Naito
Summary: Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in drug development that can be used to degrade DNA-binding proteins such as transcription factors. In this study, oligonucleotide-warheaded PROTACs were used to induce the degradation of STAT3, a hard-to-target protein, showing potential therapeutic applications against cancer.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Materials Science, Biomaterials
Takahito Ito, Wakana Hashimoto, Nobumichi Ohoka, Takashi Misawa, Takao Inoue, Ryuji Kawano, Yosuke Demizu
Summary: In this study, helical amphipathic peptides containing nonproteinogenic amino acids were designed to enhance antimicrobial activity. The relationships between antimicrobial activity, hemolytic activity, and cytotoxicity were evaluated. Peptide stp1, containing α,α-disubstituted amino acids, showed potent antimicrobial activity against multidrug-resistant bacteria without causing appreciable hemolytic activity or cytotoxicity.
ACS BIOMATERIALS SCIENCE & ENGINEERING
(2023)
Article
Infectious Diseases
Takahito Ito, Natsumi Matsunaga, Megumi Kurashima, Yosuke Demizu, Takashi Misawa
Summary: Multidrug-resistant bacteria pose a significant threat to human health, causing over 1.2 million deaths annually. Antimicrobial peptides (AMPs) have emerged as potential next-generation therapeutics to combat infectious diseases including MDRB. Our study focused on designing and synthesizing derivatives of the AMP 17KKV-Aib by replacing Lys residues with the cyclized dAA residue Api. The introduction of Api residues preserved the helical structure and antimicrobial activity, enhanced resistance to digestive enzymes, with a slight increase in hemolytic activity.
Article
Biochemistry & Molecular Biology
Keisuke Tsuchiya, Kanako Horikoshi, Minami Fujita, Motoharu Hirano, Maho Miyamoto, Hidetomo Yokoo, Yosuke Demizu
Summary: Researchers have developed hydrophobic CPPs based on the hydrophobic CPP TP10 by introducing an aliphatic carbon side chain. These stapled peptides maintained the hydrophobicity of TP10, enhanced helicity, and improved cell-penetrating efficiency. The stapled peptide F-3 with CF showed stable α-helical structure and highest cell-membrane permeability, while peptide F-4 exhibited remarkable stability in complex formation with pDNA for efficient intracellular delivery.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Takahito Ito, Hidetomo Yokoo, Takuma Kato, Mitsunobu Doi, Yosuke Demizu
Summary: In this study, a new cyclic peptide with a different amino acid arrangement was designed, leading to a change in the molecular conformation. The study demonstrates the potential to obtain diverse conformations by manipulating the arrangement of amino acids, providing a direction for developing new applications.
Article
Chemistry, Multidisciplinary
Yuki Murakami, Shoichi Ishida, Yosuke Demizu, Kei Terayama
Summary: In this study, a machine learning-assisted AMP design framework called MODAN is proposed based on multi-objective Bayesian optimization. MODAN is capable of handling various non-proteinogenic amino acids and improving both antimicrobial activity and toxicity simultaneously. Peptides with potent antimicrobial and low hemolytic activities were successfully designed through two rounds of MODAN recommendation and experimentation.
Article
Chemistry, Multidisciplinary
Motoharu Hirano, Hidetomo Yokoo, Chihiro Goto, Makoto Oba, Takashi Misawa, Yosuke Demizu
Summary: We have developed cell-penetrating stapled peptides based on the amphipathic antimicrobial peptide magainin 2 for efficient intracellular delivery of nucleic acids including pDNA, mRNA, and siRNA. The peptide st7-5_R can form stable complexes with these nucleic acids and efficiently deliver them into cells.
Article
Chemistry, Multidisciplinary
Motoharu Hirano, Hidetomo Yokoo, Chihiro Goto, Makoto Oba, Takashi Misawa, Yosuke Demizu
Summary: We have developed cell-penetrating stapled peptides based on the amphipathic antimicrobial peptide magainin 2 for efficient intracellular delivery of nucleic acids such as pDNA, mRNA, and siRNA. The stapled peptide st7-5 and its variant st7-5_R can form stable complexes with nucleic acids and successfully deliver them into cells.
