Review
Microbiology
Michael Lammers
Summary: Ac(et)ylation is a significant post-translational modification affecting essential cellular processes in all domains of life. It can occur at the ε-amino group of lysine side chains or at the α-amino group of proteins, and is involved in regulating protein function through various mechanisms including charge quenching, size alteration of lysine side chains, and interference with other modifications.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Oncology
Pedro A. Lazo
Summary: Chromatin remodeling plays a crucial role in tumor biology. Targeting epigenetic enzymes and chromatin kinases can be a novel strategy for cancer treatment. Targeting these enzymes can enhance tumor cell sensitivity to treatment and improve treatment outcomes.
Article
Cell Biology
Martin Marek, Elizabeth Ramos-Morales, Gisele F. A. Picchi-Constante, Theresa Bayer, Carina Norstrom, Daniel Herp, Policarpo A. Sales-Junior, Eloise P. Guerra-Slompo, Kristin Hausmann, Alokta Chakrabarti, Tajith B. Shaik, Annika Merz, Edouard Troesch, Karin Schmidtkunz, Samuel Goldenberg, Raymond J. Pierce, Marina M. Mourao, Manfred Jung, Johan Schultz, Wolfgang Sippl, Nilson I. T. Zanchin, Christophe Romier
Summary: The zinc-dependent histone deacetylases in the protozoan parasite Trypanosoma cruzi have significantly diverged from their human counterparts, with tcDAC2 displaying essential deacetylase activity and major structural differences. Targeting these atypical HDACs can lead to selective chemical impairment of parasites.
Review
Chemistry, Medicinal
Dan Zhang, Jifa Zhang, Yuxi Wang, Guan Wang, Pan Tang, Yun Liu, Yiwen Zhang, Liang Ouyang
Summary: Parkinson's disease (PD) is a multifactorial disease caused by a complex interplay between genetic and epigenetic factors. Recent studies have revealed the epigenetic mechanisms involved in PD, such as DNA methylation, histone modifications, and microRNA (miRNA) regulation. Epigenetic regulators could be potential therapeutic targets in neurodegenerative disorders. This review summarizes the mechanisms of epigenetic regulation in PD and discusses the use of inhibitors and activators of these regulators, as well as the neuroprotective effects of small molecule epigenetic modulators. Additionally, the contribution of miRNAs to the underlying mechanisms of PD and miRNA-based therapies are also discussed.
MEDICINAL RESEARCH REVIEWS
(2023)
Review
Chemistry, Medicinal
Jinxiao Ru, Yuxi Wang, Zijia Li, Jiaxing Wang, Changyu Ren, Jifa Zhang
Summary: This manuscript provides a comprehensive overview of the properties and biological functions of HDACs in cancer, discusses the current state of development and limitations of clinical HDAC inhibitors, and analyzes a range of innovative medicinal chemistry techniques that are applied.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Alyson M. Curry, Ian Cohen, Song Zheng, Jessica Wohlfahrt, Dawanna S. White, Dickson Donu, Yana Cen
Summary: This study focused on the development of activity-based chemical probes (ABPs) for profiling sirtuin activity in biological samples. Cyclooctyne-containing and azido-containing probes were synthesized, showing different labeling efficiency and selectivity. Azido-containing ABPs demonstrated good isoform selectivity and allowed the study of dynamic cellular protein activity change.
BIOORGANIC CHEMISTRY
(2021)
Review
Oncology
Danielle P. Johnson, Mahesh B. Chandrasekharan, Marie Dutreix, Srividya Bhaskara
Summary: Researchers are interested in targeting aberrant DNA repair in cancers in addition to transcription and replication, as inhibiting DNA repair selectively in cancer cells is crucial to overcoming survival advantages imparted by chromosomal translocations or mutations. Aberrant DNA repair pathways are potential targets for therapeutic intervention in developmental diseases and cancers.
Review
Chemistry, Medicinal
Liesbeth Everix, Elsie Neo Seane, Thomas Ebenhan, Ingeborg Goethals, Julie Bolcaen
Summary: Despite advances in multimodality therapy, the prognosis for glioblastoma (GB) is still poor. Histone deacetylase inhibitors (HDACi) have attracted attention as anti-cancer agents due to their pleiotropic effects, but their therapeutic activity is not well-defined. This review provides an overview of the current status of HDACi for GB therapy and their radiopharmaceutical targeting. Imaging HDAC expression/activity could offer insights into the role of HDAC enzymes in gliomagenesis, helping identify patients who may benefit from HDACi-targeted therapy.
Review
Biochemistry & Molecular Biology
Anna-Theresa Blasl, Sabrina Schulze, Chuan Qin, Leonie G. Graf, Robert Vogt, Michael Lammers
Summary: Ac(et)ylation of lysine side chains is a dynamic post-translational modification that regulates fundamental cellular processes and affects the ageing process of organisms. Sirtuins have been identified as mediators of the beneficial effects of caloric/dietary restriction on health or lifespan. The focus is on sirtuins and lysine acyltransferases as direct sensors and mediators of cellular metabolic state.
BIOLOGICAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Abdelhakim Bouyahya, Naoufal El Hachlafi, Tarik Aanniz, Ilhame Bourais, Hamza Mechchate, Taoufiq Benali, Mohammad Ali Shariati, Pavel Burkov, Jose M. Lorenzo, Polrat Wilairatana, Mohammad S. Mubarak, Nasreddine El Omari
Summary: Cancer is a complex pathology that can be caused by various risk factors, including epigenetic factors. Natural molecules extracted from medicinal plants have been found to inhibit the enzymatic activity of histone deacetylases (HDACs), showing potential as anti-cancer agents.
Article
Nutrition & Dietetics
Melina Mitsiogianni, Dimitrios T. Trafalis, Rodrigo Franco, Vasilis Zoumpourlis, Aglaia Pappa, Mihalis Panayiotidis
Summary: The study shows that sulforaphane and iberin can reduce cell viability and modulate histone acetylation and methylation, suggesting their potential anticancer effects in malignant melanoma by regulating the epigenetic response.
EUROPEAN JOURNAL OF NUTRITION
(2021)
Review
Pharmacology & Pharmacy
Milan Beljkas, Aleksandra Ilic, Alen Cebzan, Branko Radovic, Nemanja Djokovic, Dusan Ruzic, Katarina Nikolic, Slavica Oljacic
Summary: HDAC6 is a key regulator of the balance of acetylation of non-histone proteins, and its overexpression is associated with various malignancies. Dual-target HDAC6 inhibitors have become a new trend in cancer treatment due to the low efficacy and off-target effects of current inhibitors.
Review
Biochemistry & Molecular Biology
Maria Gkotzamanidou, Elisavet Terpou, Nikolaos Kentepozidis, Evangelos Terpos
Summary: Multiple myeloma is characterized by genomic instability and epigenetic regulation, which play important roles in its pathogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Virology
Shucheng Zheng, Fanjuan Meng, Dongli Li, Lingke Liu, Di Ge, Qing Wang, Haipeng Liu
Summary: This study functionally characterized SIRT1 in the red claw crayfish and found its involvement in white spot syndrome virus (WSSV) infection. Knocking down CqSIRT1 inhibited the transcription of the WSSV late envelope gene vp28, while enhancing deacetylase activity promoted WSSV replication. Further experiments demonstrated the interaction between CqSIRT1 and viral envelope proteins VP28, VP24, and VP26.
Article
Chemistry, Multidisciplinary
David Quach, Guanghui Tang, Jothi Anantharajan, Nithya Baburajendran, Anders Poulsen, John L. K. Wee, Priya Retna, Rong Li, Boping Liu, Doris H. Y. Tee, Perlyn Z. Kwek, Joma K. Joy, Wan-Qi Yang, Chong-Jing Zhang, Klement Foo, Thomas H. Keller, Shao Q. Yao
Summary: In this study, a carbonyl boronic acid warhead was utilized to design BCR-ABL inhibitors, targeting the catalytic lysine with improved potency against ABL kinases. Selectivity of these inhibitors largely depends on molecular recognition of the non-covalent pharmacophore, and insights into the interaction of the warhead with the catalytic lysine were provided through cocrystal structures. The off-target evaluation of compounds was performed using label-free mass spectrometry in different mammalian cells.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Beatrice Noce, Elisabetta Di Bello, Clemens Zwergel, Rossella Fioravanti, Sergio Valente, Dante Rotili, Andrea Masotti, Mohammad Salik Zeya Ansari, Daniela Trisciuoglio, Alokta Chakrabarti, Christophe Romier, Dina Robaa, Wolfgang Sippl, Manfred Jung, Cecile Haeberli, Jennifer Keiser, Antonello Mai
Summary: Schistosoma mansoni HDAC8 is a reliable target for combating schistosomiasis, but most inhibitors lack selectivity over human deacetylases and have low or no activity against the parasite. In this study, a small library of HDAC inhibitors from the lab was tested for their in vitro enzyme and biological activity. These inhibitors showed submicromolar/nanomolar potency against smHDAC8 and varied selectivity over hHDAC1 and/or hHDAC6. Some compounds exhibited high activity against larval and adult stages of S. mansoni with moderate to no toxicity in human fibroblast cells.
Article
Chemistry, Medicinal
Elisabetta Di Bello, Veronica Sian, Giulio Bontempi, Clemens Zwergel, Rossella Fioravanti, Beatrice Noce, Carola Castiello, Stefano Tomassi, Davide Corinti, Daniela Passeri, Roberto Pellicciari, Ciro Mercurio, Mario Varasi, Lucia Altucci, Marco Tripodi, Raffaele Strippoli, Angela Nebbioso, Sergio Valente, Antonello Mai
Summary: After years of research, HDAC inhibitors have been developed and approved by FDA/Chinese FDA for the treatment of cancer and non-cancer diseases. A series of novel compounds have been discovered to be effective anticancer agents, demonstrating selective inhibition of HDACs and inducing cell death and differentiation. These compounds also modulate gene and protein expression related to apoptosis and show potent antiproliferative activity in various cancer cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Francesco Fiorentino, Martina Menna, Dante Rotili, Sergio Valente, Antonello Mai
Summary: RNA methylation is a crucial mechanism for regulating gene expression and RNA maturation. METTL3, an RNA methyltransferase, plays a key role in this process by adding a methyl group to N6-adenosine of RNA. Dysregulation of METTL3 can lead to various diseases and viral infections. By studying the correlation between METTL3 and diseases, as well as analyzing the development and mode of action of known METTL3 inhibitors, we can gain a better understanding of the biological functions of this enzyme and potentially develop new therapeutics.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Jujun Zhou, Youchao Deng, Iredia D. Iyamu, John R. Horton, Dan Yu, Taraneh Hajian, Masoud Vedadi, Dante Rotili, Antonello Mai, Robert M. Blumenthal, Xing Zhang, Rong Huang, Xiaodong Cheng
Summary: We modified S-adenosyl-L-methionine (SAM) analogs to discover potent and selective inhibitors of Clostridioides difficile-specific DNA adenine MTase (CamA). Compound 11a, with a 3-phenylpropyl moiety at the adenine N6-amino group and a 3-(cyclohexylmethyl guanidine)-ethyl moiety at the sulfur atom, exhibited higher inhibitory activity against CamA compared to its parental compounds. Our study provides a hybrid approach for generating CamA inhibitors and offers potential chemical agents to investigate the mechanism and therapeutic potential of CamA in C. difficile infection.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Francesco Fiorentino, Alessio Nocentini, Dante Rotili, Claudiu T. Supuran, Antonello Mai
Summary: Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. This study investigated various drugs as potential CA activators and found that phenothiazine-based antipsychotics and tricyclic antidepressants were the most effective at activating hCA VII. These findings provide insights into the pharmacological profiles of clinically employed drugs and may contribute to the development of novel CA activators.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Michele Aventaggiato, Federica Barreca, Laura Vitiello, Simone Vespa, Sergio Valente, Dante Rotili, Antonello Mai, Lavinia Vittoria Lotti, Luigi Sansone, Matteo A. Russo, Mariano Bizzarri, Elisabetta Ferretti, Marco Tafani
Summary: Life on Earth has evolved in the presence of gravity constraint, and any change in gravity has important physiological effects. Our study demonstrates that activation of mitochondrial Sirtuin 3 (SIRT3) can reduce muscle damage caused by microgravity and preserve muscle differentiation. We simulated microgravity on a muscle and cardiac cell line and treated the cells with a newly synthesized SIRT3 activator. The results show that SIRT3 activation reduces microgravity-induced cell death and maintains muscle cell differentiation markers.
Article
Biochemistry & Molecular Biology
Francesco Fiorentino, Antonello Mai, Dante Rotili
Summary: Sirtuins are NAD+-dependent enzymes with multiple functions, including DNA repair, cell survival, metabolism, ROS detoxification, inflammation, cardiac function, and neuronal signaling. The development of sirtuin activators has gained significant interest due to their beneficial effects on health and lifespan. Structural biology has played a crucial role in discovering and characterizing these activators, providing insights into their mechanisms of action and enabling the design of more potent and selective molecules.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Editorial Material
Chemistry, Medicinal
Francesco Fiorentino, Fabrizio Carta, Dante Rotili, Antonello Mai, Claudiu T. Supuran
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Clemens Zwergel, Michele Aventaggiato, Sabrina Garbo, Elisabetta Di Bello, Bruno Fassari, Beatrice Noce, Carola Castiello, Chiara Lambona, Federica Barreca, Dante Rotili, Rossella Fioravanti, Thomas Schmalz, Michael Weyand, Amelie Niedermeier, Marco Tripodi, Gianni Colotti, Clemens Steegborn, Cecilia Battistelli, Marco Tafani, Sergio Valente, Antonello Mai
Summary: The mitochondrial protein SIRT3 plays a role in cancer, metabolism, and hypoxia-related diseases. New 1,4-dihydropyridine compounds, namely 2 and 3, have been discovered and compound 3 is a specific activator of SIRT3. Among a series of related compounds, compound 3c binds and activates SIRT3 the strongest, while compound 3d shows the best effects on enhancing glutamate dehydrogenase activity and deacetylating proteins in breast cancer cells. Compound 3d also exhibits significant anti-cancer effects in both normoxia and hypoxia conditions, reducing cell viability, clonogenicity, and migration ability.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Joana Reis, Christoph Gorgulla, Marta Massari, Sara Marchese, Sergio Valente, Beatrice Noce, Lorenzo Basile, Ricarda Toerner, Huel Cox, Thibault Viennet, Moon Hee Yang, Melissa M. Ronan, Matthew G. Rees, Jennifer A. Roth, Lucia Capasso, Angela Nebbioso, Lucia Altucci, Antonello Mai, Haribabu Arthanari, Andrea Mattevi
Summary: In this study, the authors validate inhibitors for human NOX enzymes using computational and experimental methods, opening avenues for cancer drug development and research in redox biology.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Federica Barreca, Michele Aventaggiato, Laura Vitiello, Luigi Sansone, Matteo Antonio Russo, Antonello Mai, Sergio Valente, Marco Tafani
Summary: This study suggests that activation of SIRT5 and reduction in Pi could be a valid strategy to inhibit cell proliferation by reducing glutamine metabolism and mitophagy, leading to the accumulation of ROS.