Article
Chemistry, Multidisciplinary
Yuan Liu, Xu Qian, Chunyan Ran, Longjie Li, Ting Fu, Dan Su, Sitao Xie, Weihong Tan
Summary: The selective removal of misfolded, aggregated, or aberrantly overexpressed proteins is crucial in protein-dominated biological processes. Targeted protein degradation (TPD) technology, utilizing small molecules or antibodies as protein recognition tools, has great potential in various fields. Aptamers, which are short RNA or DNA oligonucleotides, are actively used in designing and constructing TPD technology. This article provides an overview of TPD technology, its application challenges, and recent advances in aptamer-based TPD technology.
Article
Pharmacology & Pharmacy
Qian-Qian Zhou, Hai -Tao Xiao, Fan Yang, Yong-Dan Wang, Ping Li, Zu-Guo Zheng
Summary: The development and application of traditional drugs, especially inhibitors, has become the mainstream drug development. Targeted protein degradation (TPD) technology, based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), has emerged as a promising method to remove specific disease-related proteins. Different TPD strategies, such as PROTAC, MG, LYTAC, CMA-targeting chimeras, AUTAC, ATTEC, and AUTOTAC, can change undruggable protein targets in human cells to druggable, expanding the therapeutic prospect of refractory diseases.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Chunrong Yang, Yuchen Yang, Yujie Li, Qiankun Ni, Jinghong Li
Summary: Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy that shows great potential in targeting difficult-to-drug proteins. This study introduces a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy for precise and spatiotemporal control of protein degradation through X-ray radiation. The activated RT-PROTAC effectively degrades target proteins and exhibits synergistic anticancer activity with radiotherapy. This research provides an alternative approach for controlling protein degradation in vivo, offering a potential solution to minimize the systemic toxicity of PROTACs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Yue Zhong, Fanglian Chi, Hanyu Wu, Yunxiao Liu, Zhancheng Xie, Wenlong Huang, Wei Shi, Hai Qian
Summary: Targeted protein degradation technology represents a new therapeutic modality in drug discovery. Researchers are exploring optimized protein degraders to overcome the limitations of classical PROTACs and achieve more precise protein degradation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Andrew J. Tao, Gillian E. Gadbois, Stanley A. Buczynski, Fleur M. Ferguson
Summary: Targeted protein degraders are small molecules that can rapidly reduce the expression of target proteins. Recent studies have shown that degraders with specificity can be developed for subpopulations of target proteins.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Bedwyr ab Ion Thomas, H. Lois Lewis, D. Heulyn Jones, Simon E. Ward
Summary: Diseases of the central nervous system have received less attention in pharmaceutical research and development due to challenges in target validation, translational models, and clinical trial design. However, with the increase in medical need caused by longer life expectancy and higher prevalence of age-related diseases, advanced therapies are being developed for CNS diseases, including protein degradation technologies. Despite potential in gene-based therapies and antibodies, small molecules remain the main modality for brain-targeting drugs.
Review
Pharmacology & Pharmacy
Sinan Ma, Jianai Ji, Yuanyuan Tong, Yuxuan Zhu, Junwei Dou, Xian Zhang, Shicheng Xu, Tianbao Zhu, Xiaoli Xu, Qidong You, Zhengyu Jiang
Summary: The article introduces the development of proteolysis targeting chimeras (PROTACs) technology and the advantages of non-small molecule PROTACs (NSM-PROTACs), and summarizes the progress of NSM-PROTACs so far.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biochemistry & Molecular Biology
Gaoqi Weng, Chao Shen, Dongsheng Cao, Junbo Gao, Xiaowu Dong, Qiaojun He, Bo Yang, Dan Li, Jian Wu, Tingjun Hou
Summary: PROTACs, a novel therapeutic technology that selectively degrades targeted proteins, has achieved significant progress with two PROTACs in phase I clinical trials. However, the design of PROTACs remains challenging. PROTAC-DB, a web-based database, integrates structural information and experimental data of PROTACs, providing convenient querying and filtering tools for researchers.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Chemistry, Medicinal
Yu -Wei Wang, Li Lan, Min Wang, Jin-Yang Zhang, Yu -Hui Gao, Lei Shi, Li -Ping Sun
Summary: Abnormally expressed or malfunctioning proteins may damage cells, leading to diseases. Proteolysis targeting chimera (PROTAC) technology has been proven to be a superior therapeutic strategy for diseases caused by pathogenic proteins. Unlike conventional small molecule inhibitors, PROTACs are heterobifunctional small molecules that combine with E3 ligases and target proteins to form a complex, leading to the degradation of the target protein.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Siyu Chen, Jingliang Cui, Haiyan Chen, Bo Yu, Sihui Long
Summary: Targeted protein degradation is a key strategy in current cancer therapy, and Proteolysis targeting chimera (PROTAC) is a popular branch that induces target protein degradation by activating the ubiquitin-proteasome system. In addition to intracellular proteins, membrane proteins have also been reported to be degraded, and other effective membrane protein degradation strategies have emerged.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Rui Li, Miao Liu, Zhenya Yang, Jiao Li, Yuxin Gao, Ruirong Tan
Summary: PROteolysis TArgeting Chimeras (PROTACs) is an innovative technique that selectively degrades target proteins via the ubiquitin-proteasome system, offering advantages over traditional protein inhibitor drugs in terms of efficacy, selectivity, and overcoming drug resistance in cancer therapy. In this review, we comprehensively discuss the historical milestones, structures, mechanisms, and application of PROTACs in targeting tumor-related targets. We also provide a list of representative PROTACs based on CRBN, VHL, MDM2, or cIAP1 E3 ligases, as well as those undergoing clinical trials for anti-cancer activity.
Review
Chemistry, Medicinal
Anna Pasieka, Eleonora Diamanti, Elisa Uliassi, Maria Laura Bolognesi
Summary: Click chemistry and targeted protein degradation, two flourishing trends in medicinal chemistry. Can they be a winning combination? In this review, we provide the reader with selected examples offered by the combination of these two approaches trying to find a response to this question.
Article
Chemistry, Multidisciplinary
Heng Zhang, Yu Han, Yuanfan Yang, Feng Lin, Kexin Li, Linghao Kong, Hongxiang Liu, Yongjun Dang, Jian Lin, Peng R. Chen
Summary: The study introduces a covalent nanobody-based PROTAC strategy named GlueTAC for targeted membrane protein degradation with high specificity and efficiency. By developing a mass-spectrometry-based screening platform, a covalent nanobody (GlueBody) was created for proximity-enabled cross-linking with surface antigens on cancer cells, leading to the internalization and degradation of PD-L1 by the resulting GlueTAC chimera.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Guoqiang Dong, Ying Wu, Junfei Cheng, Long Chen, Rui Liu, Yu Ding, Shanchao Wu, Junhui Ma, Chunquan Sheng
Summary: ATTEC-ispinesib has been identified as an effective warhead for designing autophagosome-tethering chimeras, and it has the potential for broad applications.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Nathaniel J. Henning, Lydia Boike, Jessica N. Spradlin, Carl C. Ward, Gang Liu, Erika Zhang, Bridget P. Belcher, Scott M. Brittain, Matthew J. Hesse, Dustin Dovala, Lynn M. McGregor, Rachel Valdez Misiolek, Lindsey W. Plasschaert, David J. Rowlands, Feng Wang, Andreas O. Frank, Daniel Fuller, Abigail R. Estes, Katelyn L. Randal, Anoohya Panidapu, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, Daniel K. Nomura
Summary: Many diseases caused by aberrant protein ubiquitination and degradation could benefit from targeted protein stabilization (TPS). In this study, deubiquitinase-targeting chimeras (DUBTACs) were used to stabilize specific proteins degraded in a ubiquitin-dependent manner, leading to therapeutic benefits. Covalent chemoproteomic approaches were used to identify a ligand, EN523, that targeted a specific deubiquitinase. DUBTACs consisting of EN523 and a protein-targeting ligand were shown to stabilize the levels of disease-related proteins, showing promise for TPS.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Afzal Husain, Nasim A. Begum, Takako Taniguchi, Hisaaki Taniguchi, Maki Kobayashi, Tasuku Honjo
NATURE COMMUNICATIONS
(2016)
Article
Immunology
Azza Al Ismail, Afzal Husain, Maki Kobayashi, Tasuku Honjo, Nasim A. Begum
INTERNATIONAL IMMUNOLOGY
(2017)
Article
Biochemistry & Molecular Biology
Ghulam Jeelani, Afzal Husain, Dan Sato, Tomoyoshi Soga, Makoto Suematsu, Tomoyoshi Nozaki
Article
Infectious Diseases
Gil M. Penuliar, Atsushi Furukawa, Kumiko Nakada-Tsukui, Afzal Husain, Dan Sato, Tomoyoshi Nozaki
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2012)
Article
Multidisciplinary Sciences
Ghulam Jeelani, Dan Sato, Afzal Husain, Aleyla Escueta-de Cadiz, Masahiro Sugimoto, Tomoyoshi Soga, Makoto Suematsu, Tomoyoshi Nozaki
Article
Multidisciplinary Sciences
Jianliang Xu, Afzal Husain, Wenjun Hu, Tasuku Honjo, Maki Kobayashi
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2014)
Article
Biochemistry & Molecular Biology
Afzal Husain, Jianliang Xu, Hodaka Fujii, Mikiyo Nakata, Maki Kobayashi, Ji-Yang Wang, Jan Rehwinkel, Tasuku Honjo, Nasim A. Begum
Article
Biochemistry & Molecular Biology
Nasim A. Begum, Farazul Hague, Andre Stanlie, Afzal Husain, Samiran Mondal, Mikiyo Nakata, Takako Taniguchi, Hisaaki Taniguchi, Tasuku Honjo
Summary: Antibody class switch recombination (CSR) is a locus-specific genomic rearrangement that involves multiple factors, with Phf5a identified as a novel regulator of DNA repair in this process. Through maintaining chromatin integrity, Phf5a facilitates NHEJ-dependent DNA repair during CSR.
Review
Immunology
Asim Azhar, Nasim A. Begum, Afzal Husain
Summary: The availability and balance of dNTPs are crucial for the fidelity and processivity of DNA polymerases, affecting genomic stability and antibody gene diversification. Abnormalities in dNTP pools can impact chromosomal activities and processes involving DNA polymerases.
Review
Medicine, General & Internal
Gowhar Rashid, Nihad Ashraf Khan, Deena Elsori, Andleeb Rehman, Haleema Tanzeelah, Haleema Ahmad, Humaira Maryam, Amaan Rais, Mohd Salik Usmani, Asaad Ma Babker, Mohammad Azhar Kamal, Wael Hafez
Summary: Colorectal cancer is caused by mutations in large intestinal epithelial cells and can be detected early through biomarkers such as KRAS and ctDNA/cfDNA. While colonoscopy is the most common invasive method for diagnosing CRC, non-invasive techniques like molecular analysis of breath, urine, blood, and stool can also be used for early detection. NSAIDs have been found to have a chemopreventive impact on CRC by inhibiting cyclooxygenase enzymes and causing apoptosis in CRC cells. This review paper explores the diversity of biomarkers and detection techniques for CRC, as well as the role of NSAIDs in chemoprevention.
FRONTIERS IN MEDICINE
(2023)
Article
Biochemical Research Methods
Afreen Kamal Farooqui, Haleema Ahmad, Mohd Umar Rehmani, Afzal Husain
Summary: The polymerase chain reaction is a widely used technique in biology, and Pfu-Sso7d is a fusion DNA polymerase known for its high processivity and fidelity. This study reports a quick and cost-efficient purification protocol as well as an optimized buffer system for Pfu-Sso7d.
PROTEIN EXPRESSION AND PURIFICATION
(2023)
