Article
Biochemistry & Molecular Biology
Jakub Ptacek, Ivan Snajdr, Jiri Schimer, Zsofia Kutil, Jana Mikesova, Petra Baranova, Barbora Havlinova, Werner Tueckmantel, Pavel Majer, Alan Kozikowski, Cyril Barinka
Summary: This article compares hydroxamate-based HDAC6-selective inhibitors commonly used in the treatment of neurological and psychiatric disorders with a novel HDAC6 inhibitor containing the difluoromethyl-1,3,4-oxadiazole function (compound 7). In vitro screening revealed HDAC10 as a primary off-target for hydroxamate-based HDAC6 inhibitors, while compound 7 showed exquisite selectivity over all other HDAC isoforms. Cell-based assays showed lower potency for all compounds when using tubulin acetylation as a surrogate readout. Additionally, the limited selectivity of some HDAC6 inhibitors was shown to be linked to cytotoxicity in RPMI-8226 cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Yunjian Dai, Taofeng Wei, Yuwen Huang, Yun Bei, Haoran Lin, Zexu Shen, Lingyan Yu, Mingdong Yang, Huimin Xu, Wei He, Zheng Lin, Haibin Dai
Summary: Inhibition of HDAC9 may be a novel approach for treating depression, as it is highly expressed in the hippocampus of a mouse model of chronic restraint stress-induced depression and is associated with depression-like behavior. Furthermore, the study also found that HDAC9 interacts with Annexin A2, resulting in the development of depressive symptoms.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Zheng Guo, Yi Zhang, Ya Bao, Ziyi Huang, Xiu Gu, Guan Wang, Jianqi Li
Summary: In this study, selective HDAC6 inhibitors were designed and synthesized using thiol as the zinc-binding group instead of the commonly used hydroxamate. Compound 21, obtained through constant simplification and evolution, showed unexpectedly high selectivity and moderate potency. The utilization of pyrimidine as a linker in thiol-based HDAC6 inhibitors resulted in a novel structure.
CHEMICAL BIOLOGY & DRUG DESIGN
(2022)
Review
Chemistry, Medicinal
Mauricio T. Tavares, Alan P. Kozikowski, Sida Shen
Summary: Histone deacetylase 6 (HDAC6) is a zinc-dependent enzyme that regulates the acetylation of non-histone substrates, impacting various cellular processes. The discovery of mercaptoacetamide (MCA)-based HDAC6 inhibitors has shown promising potential due to their selectivity and lack of mutagenicity. Further research on the structure-activity relationships, selectivity, and pharmacological properties of MCA-based HDAC6 inhibitors could lead to improved drug-like properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Kairui Yue, Simin Sun, Geng Jia, Mengting Qin, Xiaohan Hou, C. James Chou, Chao Huang, Xiaoyang Li
Summary: This study reports the development of a highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which exhibits superior pharmacokinetic properties compared to current hydroxamic acid inhibitors. Structure-activity relationship analysis reveals that the presence of an ethyl group substituent in the hydrazide-based ZBG and a cap group with increased rigidity and volume enhance the HDAC6 selectivity of the designed compounds. The representative inhibitor 35m demonstrates potent HDAC6 inhibitory activity and improved pharmacokinetic properties compared to hydroxamic acid-based HDAC6 inhibitors Tubastatin A and ACY1215. Furthermore, low-dose 35m effectively decreases LPS-induced IL-1 beta release by blocking the activation of NLRP3, indicating its potential as an orally active therapeutic agent for NLRP3-related diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Ping Shi, Lan B. Hoang-Minh, Jia Tian, Alice Cheng, Reemsha Basrai, Neil Kalaria, Joseph J. Lebowitz, Habibeh Khoshbouei, Loic P. Deleyrolle, Matthew R. Sarkisian
Summary: HDAC6 plays a critical role in promoting the proliferation of glioma cells through primary cilia, and inhibiting HDAC6 activity leads to reduced tumor cell proliferative capacity and increased cell differentiation, dependent on the presence of cilia in the cells.
Article
Biochemistry & Molecular Biology
Hue Thi Buu Bui, Phuong Hong Nguyen, Quan Minh Pham, Hoa Phuong Tran, De Quang Tran, Hosun Jung, Quang Vinh Hong, Quoc Cuong Nguyen, Quy Phu Nguyen, Hieu Trong Le, Su-Geun Yang
Summary: This study reports a group of novel hydroxamic acid-based histone deacetylase inhibitors, among which compound 8 shows antiproliferative activity against cancer cells and selective inhibition of HDAC6.
Article
Biochemistry & Molecular Biology
Hye Sun Shin, Yuri Lee, Mi Hee Shin, Soo Ick Cho, Christos C. Zouboulis, Min Kyoung Kim, Dong Hun Lee, Jin Ho Chung
Summary: Proper regulation of histone acetylation is crucial for sebocyte lipogenesis, with inhibitors of p300 histone acetyltransferase leading to decreased expression of key lipogenic genes and decreased lipid droplet formation. In contrast, inhibition of histone deacetylase promotes lipogenesis by increasing the expression of these genes. These findings suggest a potential therapeutic strategy for skin diseases related to excess sebum production.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Longlong Wang, Etori Aguiar Moreira, Georg Kempf, Yasuyuki Miyake, Blandina I. Oliveira Esteves, Amal Fahmi, Jonas Schaefer, Birgit Dreier, Yohei Yamauchi, Marco P. Alves, Andreas Plueckthun, Patrick Matthias
Summary: The deacetylase HDAC6 has tandem catalytic domains and a zinc finger domain binding ubiquitin, which promotes the formation of aggresomes and stress granules. Influenza A virus subverts this pathway to facilitate infection. Designed ankyrin repeat proteins (DARPins) targeting the ZnF can impair viral infection and reduce the formation of SGs and aggresomes.
Review
Oncology
Fengyi Guo, Hongjing Wang
Summary: This review summarizes the classification and mechanisms of action of histone deacetylase and the clinical application of their inhibitors in ovarian cancer. Histone deacetylase inhibitors show promising potential as anti-cancer drugs, and combination therapy with other anticancer drugs for synergistic effects can improve efficacy.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Wenkai Zhou, Jiaming Wang, Xin Wang, Bingjing Wang, Zhehui Zhao, Jie Fu, Yan Wang, Xuan Zhang, Ping Zhu, Minghong Jiang, Xuetao Cao
Summary: HDAC10 plays an important role in immune response by inhibiting the production of type I interferon through regulating the phosphorylation of IRF3. Deficiency in HDAC10 leads to enhanced antiviral response by promoting the expression of type I interferons and interferon-stimulated genes.
Article
Cell Biology
Onsurang Wattanathamsan, Naphat Chantaravisoot, Piriya Wongkongkathep, Sakkarin Kungsukool, Paninee Chetprayoon, Pithi Chanvorachote, Chanida Vinayanuwattikun, Varisa Pongrakhananon
Summary: HDAC6 is upregulated in lung cancer and is associated with poor prognosis. Inhibition of HDAC6 results in increased tubulin acetylation and suppression of lung cancer cell growth.
JOURNAL OF BIOMEDICAL SCIENCE
(2023)
Article
Immunology
Jie Wang, Ke-yong Tian, Ying Fang, Hui-min Chang, Ya-nan Han, Fu-quan Chen
Summary: The study demonstrated that SFN can protect rats from cisplatin-induced hearing loss by reducing outer hair cell loss and restoring auditory brainstem response threshold shifts. In vitro experiments also showed that SFN can reverse cisplatin-induced ciliary morphology changes and alterations in HDAC protein expression.
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Andromachi Pouikli, Monika Maleszewska, Swati Parekh, Ming Yang, Chrysa Nikopoulou, Juan Jose Bonfiglio, Constantine Mylonas, Tonantzi Sandoval, Anna-Lena Schumacher, Yvonne Hinze, Ivan Matic, Christian Frezza, Peter Tessarz
Summary: This study reveals the impact of normal oxygen levels on the differentiation of bone-derived mesenchymal stem cells. High oxygen concentration promotes chromatin compaction and histone hypo-acetylation, resulting in osteogenic defects. Additionally, decreased activity of citrate carrier leads to the accumulation of acetyl-CoA inside mitochondria. Restoring cytosolic acetyl-CoA levels rescues the osteogenic defects.
Article
Agronomy
Qin Lu, Yan Li, Jing Liao, Zhaohong Ni, Shunchao Xia, Maofa Yang, Haiyin Li, Jianjun Guo
Summary: This study investigated the role of histone H3 acetylation in diapause of the cotton bollworm and found that it is closely related to pupal diapause, suggesting its potential as a target for pest control.
PEST MANAGEMENT SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Judit Olah, Sandor Szunyogh, Tibor Szenasi, tamas Szaniszlo, Adel Szabo, Attila Lehotzky, Timea Berki, Laszlo Nyitray, Judit Ovadi
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2019)
Review
Cell Biology
Judit Olah, Attila Lehotzky, Sandor Szunyogh, Tibor Szenasi, Ferenc Orosz, Judit Ovadi
Article
Biochemistry & Molecular Biology
Matthias Schiedel, Attila Lehotzky, Sandor Szunyogh, Judit Olah, Soeren Hammelmann, Nathalie Woessner, Dina Robaa, Oliver Einsle, Wolfgang Sippl, Judit Ovadi, Manfred Jung
Article
Biochemistry & Molecular Biology
Attila Lehotzky, Judit Olah, Janos Tibor Fekete, Tibor Szenasi, Edit Szabo, Balazs Gyorffy, Gyorgy Varady, Judit Ovadi
Summary: The pathological association of SYN and TPPP/p25 contributes to the etiology of synucleinopathies, and their hetero-association after uptake by human cells inhibits autophagy, hindering SYN degradation. Fragments of TPPP/p25 have been shown to prevent the pathological assembly of the hallmark proteins, suggesting a potential strategy for preventing pathological SYN assemblies.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Cell Biology
Victor Norris, Judit Ovadi
Summary: The emergence of the novel coronavirus SARS-CoV-2 has caused significant healthcare and socioeconomic problems worldwide, with uncertainties surrounding its rapid spread and severe health impacts. While progress is being made in developing vaccines and medications, the appearance of new, more aggressive mutants poses challenges for treatment.
Review
Biochemistry & Molecular Biology
Judit Olah, Tibor Szenasi, Attila Lehotzky, Victor Norris, Judit Ovadi
Summary: Protein-protein interactions (PPIs) play a crucial role in fundamental processes and are associated with pathological conditions. However, discovering drugs that can modulate PPIs poses challenges and limitations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Judit Olah, Attila Lehotzky, Tibor Szenasi, Judit Ovadi
Summary: DJ-1, a multi-functional protein with antioxidant properties, protects dopaminergic neurons against Parkinson's disease by inhibiting the toxic assembly of SYN promoted by TPPP/p25. The interaction of DJ-1 with TPPP/p25 hinders the pathology of SYN with TPPP/p25, leading to decreased intracellular fluorescence and increased proteolytic degradation of SYN complexed with TPPP/p25. This study reveals a new protective function of DJ-1 against toxic SYN assemblies in living human cells.
Article
Cell Biology
Judit Olah, Attila Lehotzky, Tibor Szenasi, Timea Berki, Judit Ovadi
Summary: TPPP3, similar to TPPP1, modulates microtubule organization but does not bind to SYN, thus inhibiting SYN aggregation and potentially serving as an agent for developing anti-Parkinson's drugs.
Article
Biochemistry & Molecular Biology
Istvan Horvath, Khadra A. Mohamed, Ranjeet Kumar, Pernilla Wittung-Stafshede
Summary: The assembly of alpha-synuclein into amyloid fibers leads to Lewy body deposits and neuronal degeneration in Parkinson's disease patients. Recent studies have shown that these amyloids can catalyze the hydrolysis of certain bonds, which can affect the metabolite composition in cells. This finding may have implications for disease progression. Evaluation: 8/10.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)