Article
Chemistry, Medicinal
Luan Carvalho Martins, Renata Barbosa de Oliveira, Jeronimo Lameira, Rafaela Salgado Ferreira
Summary: Trypanosoma cruzi is a parasite that causes Chagas disease, infecting millions of people worldwide, mostly in Latin America. Cruzain, the main cysteine protease of T. cruzi, is a validated target for developing drug candidates for Chagas disease. This study investigated the covalent inhibition mechanism of cruzain by a thiosemicarbazone-based inhibitor, providing insights into the binding modes and reaction mechanism.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Carla Di Chio, Santo Previti, Giorgio Amendola, Rahul Ravichandran, Annika Wagner, Sandro Cosconati, Ute A. Hellmich, Tanja Schirmeister, Maria Zappala, Roberta Ettari
Summary: In this study, a new series of dipeptide nitriles were developed as reversible rhodesain inhibitors at a nanomolar level. These compounds were shown to directly bind to the active site of rhodesain and act as competitive inhibitors. The most promising compounds exhibited high binding affinity and good antiparasitic activity, making them potential lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Carla Di Chio, Santo Previti, Fabiola De Luca, Marta Bogacz, Collin Zimmer, Annika Wagner, Tanja Schirmeister, Maria Zappala, Roberta Ettari
Summary: In this study, we found that the combination of the synthetic inhibitor CD24 and curcumin from Curcuma longa L. demonstrated a synergistic effect in inhibiting the activity of rhodesain. Our results also showed that the combination of the two inhibitors had a greater antitrypanosomal activity compared to CD24 alone.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
William J. Robinson, Annie E. Taylor, Solange Lauga-Cami, George W. Weaver, Randolph Rj Arroo, Marcel Kaiser, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Kuldip Singh, Tanja Schirmeister, Adolfo Botana, Chatchakorn Eurtivong, Avninder S. Bhambra
Summary: Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, with current therapy limitations and the need for further investigation. Novel anti-trypanosomal compounds show promising potential, providing scaffolds for future drug development targeting the disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Santo Previti, Roberta Ettari, Carla Di Chio, Jenny Legac, Marta Bogacz, Collin Zimmer, Tanja Schirmeister, Philip J. Rosenthal, Maria Zappala
Summary: In recent decades, potent inhibitors of cysteine proteases FP-2 and RD have been discovered. The roles of amino acids in the S3 pocket were not widely investigated. The study reports on the synthesis and evaluation of novel Michael acceptors, which showed promising inhibitory properties against FP-2 and RD in cell-based assays.
BIOORGANIC CHEMISTRY
(2023)
Article
Nanoscience & Nanotechnology
Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Kelly Q. Schoenfelt, Alexandria Hoffman, Ariane Blank, Blake McBeth, Natalie Pulliam, Catherine A. Reardon, Swati A. Kulkarni, Tomas Vaisar, Andrea Ballabio, Yamuna Krishnan, Lev Becker
Summary: Tumour-associated macrophages (TAMs) have hyperactive cysteine protease activity in their lysosomes, impairing antigen cross-presentation and CD8(+) T cell activation. A DNA nanodevice (E64-DNA) targets TAM lysosomes in mice, inhibiting lysosomal cysteine proteases, enhancing antigen cross-presentation, and suppressing tumour growth via CD8(+) T cells. When combined with cyclophosphamide, E64-DNA leads to sustained tumour regression in a triple-negative-breast-cancer model, showcasing the potential of DNA nanodevices for immunomodulation in vivo.
NATURE NANOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Wagner A. S. Judice, Leticia Silva Ferraz, Rayssa de Mello Lopes, Luan dos Santos Vianna, Fabio da Silva Siqueira, Juliana F. Di Iorio, Laura de Azevedo Maffeis Dalzoto, Mariana Nascimento Romero Trujilho, Taiz dos Reis Santos, Mauricio F. M. Machado, Tiago Rodrigues
Summary: Leishmaniasis and trypanosomiasis are endemic neglected diseases in South America and Africa, posing a significant public health problem. Current therapeutic options have limitations, leading to the search for new targets and treatments. Cysteine proteases are being investigated as promising targets for drug discovery against protozoal neglected diseases.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Carina Lemke, Adela Jilkova, Dominic Ferber, Annett Braune, Anja On, Patrick Johe, Alena Zikova, Tanja Schirmeister, Michael Mares, Martin Horn, Michael Gutschow
Summary: We developed a bimodal rhodesain probe that can detect and quantify rhodesain with high sensitivity, and used it for inhibitor screening. This probe provides a new tool for studying Trypanosoma pathobiochemistry and antitrypanosomal drug discovery.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Peter Gorilak, Martina Pruzincova, Hana Vachova, Marie Olsinova, Marketa Schmidt Cernohorska, Vladimir Varga
Summary: Expansion microscopy (ExM) is a powerful super-resolution method that faithfully reproduces cell morphology and complements electron microscopy approaches by providing more quantitative data. It can identify rare cell types in a population and visualize proteins tagged with small epitope tags, facilitating studies on cell structures.
Article
Biochemistry & Molecular Biology
Yi-Zhen Zheng, Jingxuan Cui, Yung-Lin Wang, Szu-Jo Huang, En-Chi Lin, Sheng-Cih Huang, Jeffrey D. Rudolf, Xiaohui Yan, Chin-Yuan Chang
Summary: This study reports the BLM-binding site and catalytic mechanism of human bleomycin hydrolase, which is involved in BLM detoxification and drug resistance.
Article
Chemistry, Multidisciplinary
Jessica Alves Nunes, Fabricia Nunes da Silva, Elany Barbosa da Silva, Clara Andrezza Crisostomo Bezerra Costa, Johnnatan Duarte de Freitas, Francisco Jaime Bezerra Mendonca-Junior, Miriam Aparecida Giardini, Jair Lage de Siqueira-Neto, James H. McKerrow, Thaiz Rodrigues Teixeira, Louis William Odeesho, Conor R. Caffrey, Silvia Helena Cardoso, Edeildo Ferreira da Silva-Junior
Summary: A virtual fragment-based drug design approach was used to develop coumarin-based analogs that can inhibit two cysteine proteases of Trypanosoma cruzi and T. brucei. One compound, FN-27, showed inhibitory activity against both CRZ and TbrCATL, as well as trypanocidal activity against T. cruzi-infected cells. Another compound, FN-10, exhibited activity against T. brucei trypomastigotes but did not inhibit CRZ or TbrCATL. Molecular dynamics simulations confirmed the binding modes of FN-27 with both proteases. These findings are valuable for the development of novel natural-product-based inhibitors targeting these cysteine proteases.
NEW JOURNAL OF CHEMISTRY
(2023)
Article
Immunology
Edel Perez-Lopez, Md Musharaf Hossain, Yangdou Wei, Christopher D. Todd, Peta C. Bonham-Smith
Summary: Plant pathogen effector protein SSPbP53 is a conserved apoplastic cystatin-like protein in Plasmodiophora brassicae, which interacts with and inhibits cruciferous papain-like cysteine proteases in order to induce clubroot susceptibility in susceptible host Brassicas.
Review
Chemistry, Multidisciplinary
David Drew, Rachel A. North, Kumar Nagarathinam, Mikio Tanabe
Summary: The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters, responsible for transporting a wide range of substrates with remarkable diversity and complex gating mechanisms. Studies have shown that residues far from the substrate binding site in MFS transporters can be just as important, and some have evolved to form unique complexes. Through in-depth descriptions of glucose transporters and multidrug resistance antiporters, novel refinements to the rocker-switch alternating-access model have been proposed.
Article
Oncology
Khushwant Singh, Pramod K. Gautam
Summary: This study establishes a reproducible and healthy multicellular 3D spheroid culture with macrophage infiltrates to mimic the tumor microenvironment and modulate the drug's efficacy on cancer cells. Results show that tumor cells undergo a metabolic shift in the presence of macrophages, and there is a shift in M0 macrophages towards tumor-associated macrophages. In addition, macrophages are involved in regulating the expression of HIF-1 alpha, HSP70, and ECM degradation cysteine proteases.
Article
Multidisciplinary Sciences
Vida Strancar, Katarina P. van Midden, Daniel Krahn, Kyoko Morimoto, Marko Novinec, Christiane Funk, Simon Stael, Christopher J. Schofield, Marina Klemencic, Renier A. L. van der Hoorn
Summary: This study developed activity-based probes for the three main types of Metacaspases and demonstrated the essential role of calcium in the activation process. The findings suggest the formation of active, unprocessed intermediates upon calcium binding before precursor protein maturation.
Article
Cell Biology
Ana L. Valenciano, Aaron C. Ramsey, Zachary B. Mackey
Article
Biochemistry & Molecular Biology
Ana L. Valenciano, Aaron C. Ramsey, Webster L. Santos, Zachary B. Mackey
BIOORGANIC & MEDICINAL CHEMISTRY
(2016)
Article
Cell Biology
Ana L. Valenciano, Giselle M. Knudsen, Zachary B. Mackey
Article
Microbiology
Momar Ndao, Milli Nath-Chowdhury, Mohammed Sajid, Victoria Marcus, Susan T. Mashiyama, Judy Sakanari, Eric Chow, Zachary Mackey, Kirkwood M. Land, Matthew P. Jacobson, Chakrapani Kalyanaraman, James H. McKerrow, Michael J. Arrowood, Conor R. Caffrey
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2013)
Article
Chemistry, Medicinal
Joao Lavrado, Zachary Mackey, Elizabeth Hansell, James H. McKerrow, Alexandra Paulo, Rui Moreira
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2012)
Article
Biotechnology & Applied Microbiology
Chao-Lin Liu, Chia-Rui Shen, Fong-Fu Hsu, Jeen-Kuan Chen, Pei-Tzu Wu, Shang-Hsin Guo, Wen-Chien Lee, Feng-Wei Yu, Zachary B. Mackey, John Turk, Michael L. Gross
BIOTECHNOLOGY PROGRESS
(2009)
Article
Biochemistry & Molecular Biology
Zachary B. Mackey, Kyriacos Koupparis, Mari Nishino, James H. McKerrow
CHEMICAL BIOLOGY & DRUG DESIGN
(2011)
Review
Pharmacology & Pharmacy
Patricia S. Doyle, Mohamed Sajid, Theresa O'Brien, Kelly DuBois, Juan C. Engel, Zachary B. Mackey, Sharon Reed
CURRENT PHARMACEUTICAL DESIGN
(2008)
Article
Biochemistry & Molecular Biology
Theresa C. O'Brien, Zachary B. Mackey, Richard D. Fetter, Youngchool Choe, Anthony J. O'Donoghue, Min Zhou, Charles S. Craik, Conor R. Caffrey, James H. McKerrow
JOURNAL OF BIOLOGICAL CHEMISTRY
(2008)
Article
Plant Sciences
Laura M. Sanchez, Giselle M. Knudsen, Claudia Helbig, Geraldine De Muylder, Samantha M. Mascuch, Zachary B. Mackey, Lena Gerwick, Christine Clayton, James H. McKerrow, Roger G. Linington
JOURNAL OF NATURAL PRODUCTS
(2013)
Article
Multidisciplinary Sciences
Ute Frevert, Alexandru Movila, Olga V. Nikolskaia, Jayne Raper, Zachary B. Mackey, Maha Abdulla, James McKerrow, Dennis J. Grab
Article
Infectious Diseases
Chiung-Kuang Chen, Patricia S. Doyle, Liudmila V. Yermalitskaya, Zachary B. Mackey, Kenny K. H. Ang, James H. McKerrow, Larissa M. Podust
PLOS NEGLECTED TROPICAL DISEASES
(2009)
Article
Infectious Diseases
Kenny K. H. Ang, Joseline Ratnam, Jiri Gut, Jennifer Legac, Elizabeth Hansell, Zachary B. Mackey, Katarzyna M. Skrzypczynska, Anjan Debnath, Juan C. Engel, Philip J. Rosenthal, James H. McKerrow, Michelle R. Arkin, Adam R. Renslo
PLOS NEGLECTED TROPICAL DISEASES
(2011)
Article
Chemistry, Medicinal
Awotunde J. Oluwafemi, Emmanuel O. Okanla, Pelayo Camps, Diego Munoz-Torrero, Zachary B. Mackey, Peter K. Chiang, Scott Seville, Colin W. Wright
NATURAL PRODUCT COMMUNICATIONS
(2009)