Article
Multidisciplinary Sciences
Kevin Lou, Douglas R. Wassarman, Tangpo Yang, YiTing Paung, Ziyang Zhang, Thomas A. O'Loughlin, Megan K. Moore, Regina K. Egan, Patricia Greninger, Cyril H. Benes, Markus A. Seeliger, Jack Taunton, Luke A. Gilbert, Kevan M. Shokat
Summary: The traditional search for cell-permeable drugs has focused on small, nonpolar, rigid chemical structures. However, emerging therapeutic strategies have introduced flexible chemical entities composed of multiple ligands. This study identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulate the cell permeability of specific inhibitors. The study also found that IFITMs moderately assist certain proteolysis-targeting chimeras and investigated the physicochemical requirements for involvement in this uptake pathway.
Article
Chemistry, Medicinal
Nieves Martinez-Peinado, Alvaro Lorente-Macias, Alejandro Garcia-Salguero, Nuria Cortes-Serra, Angel Fenollar-Collado, Albert Ros-Lucas, Joaquim Gascon, Maria-Jesus Pinazo, Ignacio J. Molina, Asier Unciti-Broceta, Juan J. Diaz-Mochon, Maria J. Pineda de las Infantas y Villatoro, Luis Izquierdo, Julio Alonso-Padilla
Summary: Malaria and Chagas disease are significant global health problems, but current treatments have limitations such as lack of efficacy, toxic side effects, and drug resistance. This study identified two novel purine-based compounds with potential anti-parasitic activity against Plasmodium spp. and Trypanosoma cruzi, providing a potential avenue for the development of new drugs.
Article
Biochemistry & Molecular Biology
Cheyene Almeida Celestino Menozzi, Rodolfo Rodrigo Florido Franca, Pedro Henrique Luccas, Mayara dos Santos Baptista, Tacio Vinicio Amorim Fernandes, Lucas Villas Boas Hoelz, Policarpo Ademar Sales Junior, Silvane Maria Fonseca Murta, Alvaro Romanha, Barbara Verena Dias Galvao, Marcela de Oliveira Macedo, Alana da Cunha Goldstein, Carlos Fernando Araujo-Lima, Israel Felzenszwalb, Maria Cristina Nonato, Frederico Silva Castelo-Branco, Nubia Boechat
Summary: The study successfully synthesized and evaluated new nitrotriazole analogs as potential candidates for Chagas disease drug development. The compounds showed significant inhibitory effects against Trypanosoma cruzi, with nitrotriazoles being more potent than nitroimidazoles and triazoles. The compounds also demonstrated potential for action via nitroreductase activation, showing no mutagenic potential and a low potential for hepatotoxicity.
Article
Biochemistry & Molecular Biology
Florencia Mosquillo, Gonzalo Scalese, Rodrigo Moreira, Pablo A. Denis, Ignacio Machado, Margot Paulino, Dinorah Gambino, Leticia Perez-Diaz
Summary: The current treatment for Chagas' disease using Nifurtimox and Benznidazol has limitations, highlighting the need for new drugs. Two metal-based compounds, Pd-dppf-mpo and Pt-dppf-mpo, were characterized and found to have trypanocidal activity. Through omics studies and validation experiments, it was determined that these compounds inhibit the enzymes phosphomevalonate kinase and lanosterol 14-α-demethylase to exert their therapeutic effects.
Article
Pharmacology & Pharmacy
Christian Espinosa-Bustos, Mariana Ortiz Perez, Alonzo Gonzalez-Gonzalez, Ana Maria Zarate, Gildardo Rivera, Javier A. Belmont-Diaz, Emma Saavedra, Mauricio A. Cuellar, Karina Vazquez, Cristian O. Salas
Summary: In this study, a series of new amino naphthoquinone derivatives were synthesized and evaluated for their activity against Trypanosoma cruzi strains. Compounds 2e and 7j showed the lowest IC50 values and 7j exhibited higher activity and selectivity than the reference drug benznidazole. Molecular docking studies revealed that 7j had a good interaction profile on T. cruzi trypanothione reductase (TcTR) and it was predicted to have a favorable pharmacokinetic profile for oral administration.
Article
Pharmacology & Pharmacy
Ruben Martin-Escolano, Daniel Molina-Carreno, Javier Martin-Escolano, M. Paz Clares, Cristina Galiana-Rosello, Jorge Gonzalez-Garcia, Nuria Cirauqui, Jose M. Llinares, Maria Jose Rosales, Enrique Garcia-Espana, Clotilde Marin
Summary: Chagas disease, caused by Trypanosoma cruzi, is a potentially fatal infection that was previously limited to Latin America but has now become widespread globally. This study identified new effective agents against T. cruzi and evaluated their efficacy in vivo. Compound 15 was identified as a potential candidate for the development of new therapies for Chagas disease.
Article
Immunology
Marianne Rocha-Hasler, Gabriel Melo de Oliveira, Aline Nefertiti da Gama, Ludmila Ferreira de Almeida Fiuza, Anna Frieda Fesser, Monica Cal, Romina Rocchetti, Raiza Brandao Peres, Xue Li Guan, Marcel Kaiser, Maria de Nazare Correia Soeiro, Pascal Maser
Summary: The study found that treatment with posaconazole alone in chronic Chagas disease patients resulted in a high relapse rate, prompting the search for suitable combination partners such as inhibitors of sterol and sphingolipid biosynthetic enzymes. In vitro and in vivo experiments revealed that the combination of tomatidine (TH) with posaconazole showed synergistic effects against Trypanosoma cruzi, indicating a potential for improved treatment outcomes.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Immunology
Juan Cruz Gamba, Carolina Roldan, Estefania Prochetto, Giuliana Lupi, Ivan Bontempi, Carolina Veronica Poncini, Monica Vermeulen, Ana Rosa Perez, Ivan Marcipar, Gabriel Cabrera
Summary: The study demonstrates the significant influence of MDSCs on the immune response during T. cruzi infection, even in vaccinated mice, impacting various immune cell populations. Targeting MDSCs may be an effective tool in vaccine design against T. cruzi and potentially other conditions characterized by immune system subversion.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Marilia L. Cirqueira, Leandro O. Bortot, Mayte Bolean, Mariana A. A. Aleixo, Pedro H. Luccas, Antonio J. Costa-Filho, Ana Paula Ramos, Pietro Ciancaglini, M. Cristina Nonato
Summary: Due to its severe burden and geographic distribution, Chagas disease has a significant social and economic impact on low-income countries. This study aims to understand the role of TcNTR in the basic parasite biology, investigate its potential as a drug target, and contribute to the fight against neglected tropical diseases. The results showed that TcNTR interacts with membranes, with a preference for those containing cardiolipin, and a 23-residue long insertion is involved in enzyme specificity and protein-membrane interaction.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Biochemistry & Molecular Biology
Naiara Dutra Barroso Gomes, Emanuel Paula Magalhaes, Lyanna Rodrigues Ribeiro, John Washington Cavalcante, Marcelo Morais Gomes Maia, Felipe Ramon Cunha da Silva, Arif Ali, Marcia Machado Marinho, Emmanuel Silva Marinho, Helcio Silva dos Santos, Alice Maria Costa Martins, Ramon Roseo Paula Pessoa Bezerra de Menezes
Summary: This study evaluated the activity of synthetic p-aminochalcones against T. cruzi and found that they have a trypanocidal effect by causing membrane damage and oxidative stress. Their mechanism of action may be related to inhibition of cruzain and TR.
BIOORGANIC CHEMISTRY
(2023)
Article
Immunology
Carezza Botto-Mahan, Juana P. Correa, Raul Araya-Donoso, Francisca Farias, Esteban San Juan, Nicol Quiroga, Ricardo Campos-Soto, Claudio Reyes-Olivares, Daniel Gonzalez-Acuna
Summary: In this study, we assessed 4 lizard species in Chile for Trypanosoma cruzi and found that all species were infected. We also discovered that one species had the ability to transmit the protozoan, highlighting their role as reservoirs for T. cruzi.
EMERGING INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Ivan Beltran-Hortelano, Veronica Alcolea, Maria Font, Silvia Perez-Silanes
Summary: This article provides an overview of validated targets involved in various pathways of the Trypanosoma cruzi parasite and explores the molecular basis for finding new effective treatments for Chagas disease. The review also compiles all reported inhibitors against these targets, serving as a reference for future research in this field.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Immunology
Jose L. Saenz-Garcia, Beatriz S. Borges, Normanda Souza-Melo, Luiz V. Machado, Juliana S. Miranda, Lisandro Alfonso Pacheco-Lugo, Nilmar S. Moretti, Richard Wheleer, Lia C. Soares Medeiros, Wanderson D. DaRocha
Summary: The flagellum of Trypanosomatids contributes to multiple functions, and this study explores the role of Trypanin in T. cruzi. The deletion of Trypanin affects the growth and motility of T. cruzi epimastigotes, as well as their infection capacity.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Immunology
Lucia Lopez, Maria Laura Chiribao, Magali C. Girard, Karina A. Gomez, Paula Carasi, Marisa Fernandez, Yolanda Hernandez, Carlos Robello, Teresa Freire, Maria Dolores Pineyro
Summary: The study showed that c-TXNPx induces the recruitment of IL-12/23p40-producing innate antigen-presenting cells and promotes a strong specific Th1 immune response, while c-TXNPxC52S does not. The presence of peroxidatic cysteine is essential for the peroxidase activity and quaternary structure of the protein.
Review
Pharmacology & Pharmacy
Vincent Blay, Bhairavi Tolani, Sunita P. Ho, Michelle R. Arkin
DRUG DISCOVERY TODAY
(2020)
Article
Chemistry, Medicinal
Xavier Guillory, Madita Wolter, Seppe Leysen, Joao Filipe Neves, Ave Kuusk, Sylvia Genet, Bente Somsen, John Kenneth Morrow, Emma Rivers, Lotte van Beek, Joe Patel, Robert Goodnow, Heike Schoenherr, Nathan Fuller, Qing Cao, Richard G. Doveston, Luc Brunsveld, Michelle R. Arkin, Paola Castaldi, Helen Boyd, Isabelle Landrieu, Hongming Chen, Christian Ottmann
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Correction
Immunology
Andrew S. Mendiola, Jae Kyu Ryu, Sophia Bardehle, Anke Meyer-Franke, Kenny Kean-Hooi Ang, Chris Wilson, Kim M. Baeten, Kristina Hanspers, Mario Merlini, Sean Thomas, Mark A. Petersen, Alexander Williams, Reuben Thomas, Victoria A. Rafalski, Rosa Meza-Acevedo, Reshmi Tognatta, Zhaoqi Yan, Samuel J. Pfaff, Michael R. Machado, Catherine Bedard, Pamela E. Rios Coronado, Xiqian Jiang, Jin Wang, Michael A. Pleiss, Ari J. Green, Scott S. Zamvil, Alexander R. Pico, Benoit G. Bruneau, Michelle R. Arkin, Katerina Akassoglou
Article
Biochemical Research Methods
May H. Abdel Aziz, Yao Fan, Lijun Liu, Mark M. Moasser, Haian Fu, Natalia Jura, Michelle R. Arkin
Summary: This study evaluated the use of Pichia pastoris as a host for expression of human kinases and showed that addition of the VLK domain improved expression and decreased aggregation of certain kinases. Some kinases were purified with good yield, purity, and comparable activity to commercially available versions.
PROTEIN EXPRESSION AND PURIFICATION
(2021)
Article
Biochemistry & Molecular Biology
Eline Sijbesma, Bente A. Somsen, Galen P. Miley, Iris A. Leijten-van de Gevel, Luc Brunsveld, Michelle R. Arkin, Christian Ottmann
ACS CHEMICAL BIOLOGY
(2020)
Article
Microbiology
Rahul Tyagi, Christina A. Bulman, Fidelis Cho-Ngwa, Chelsea Fischer, Chris Marcellino, Michelle R. Arkin, James H. McKerrow, Case W. McNamara, Matthew Mahoney, Nancy Tricoche, Shabnam Jawahar, James W. Janetka, Sara Lustigman, Judy Sakanari, Makedonka Mitreva
Summary: 18 hits with anti-macrofilaricidal activity were identified, with azoles and aspartic protease inhibitors being prioritized for further study. These drugs showed activity against Onchocerca spp. as well, with the potential to identify selective drugs that prevent adverse events in co-infected individuals.
Article
Chemistry, Medicinal
Eline Sijbesma, Kenneth K. Hallenbeck, Sebastian A. Andrei, Reanne R. Rust, Joris M. C. Adriaans, Luc Brunsveld, Michelle R. Arkin, Christian Ottmann
Summary: The systematic discovery of functional fragments that bind to the composite interface of protein complexes is a critical step towards developing orthosteric stabilizers for protein-protein interactions (PPIs). By evaluating structure-activity relationships, it was found that covalent fragments engaging a relatively large and exposed binding pocket at the protein/peptide interface with a molecular glue mode of action can stabilize PPIs.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Marcus Y. Chin, Anand R. Patwardhan, Kean-Hooi Ang, Austin L. Wang, Carolina Alquezar, Mackenzie Welch, Phi T Nguyen, Michael Grabe, Anna Molofsky, Michelle R. Arkin, Aimee W. Kao
Summary: A novel genetically encoded fluorescent protein-based pH biosensor called FIRE-pHLy was designed to better understand lysosomal pH, enabling ratiometric quantification and targeting lysosomes with LAMP1. The biosensor reported lumenal pH between 3.5 and 6.0 with mTFP1 and enabled quantification of the alkalinizing response to bafilomycin Al in various cellular models. FIRE-pHLy is a specific, robust, and versatile lysosomal pH biosensor with broad applications in investigating pH dynamics in aging- and lysosome-related diseases and lysosome-based drug discovery.
Article
Biochemistry & Molecular Biology
Marcus Y. Chin, Kean-Hooi Ang, Julia Davies, Carolina Alquezar, Virginia G. Garda, Brendan Rooney, Kun Leng, Martin Kampmann, Michelle R. Arkin, Aimee W. Kao
Summary: The study aimed to identify small molecules that acidify lysosomal pH and molecular targets/pathways that regulate lysosomal pH. Using a new lysosomal pH biosensor, a high-throughput screening assay identified two compounds, OSI-027 and PP242, as top acidifying hits, which may be used to investigate potential therapeutic pathways for neurodegenerative diseases such as autophagy activation and lysosomal acidification.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Ziwen Jiang, Yu-Hsuan Kuo, Mengqi Zhong, Jianchao Zhang, Xin X. Zhou, Lijuan Xing, James A. Wells, Yanzhuang Wang, Michelle R. Arkin
Summary: Protein-protein interactions (PPIs) play crucial roles in cellular signaling and functions. Precise modulation of PPIs can help understand their roles in cellular events and be therapeutically valuable. In this study, an antibody fragment-based modulator for the PPI between p97 and its adaptor protein NSFL1C was developed, demonstrating its potential application in therapeutic interventions by disrupting specific intracellular PPIs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Yinyan Tang, Amber Kay, Ziwen Jiang, Michelle R. Arkin
Summary: Autophagy is a cellular process that degrades unwanted proteins and organdies by lysosomes. The interaction between LC3B and ATG4b is studied in this research, and it is found that LC3B-115, the core of LC3B, binds tightly to full-length ATG4b and inhibits its cleavage of pro-LC3B. The C-terminal tail of ATG4b contributes significantly to the binding affinity of LC3B-ATG4b interaction and wraps around the LC3B-ubiquitin core. These findings support a bipartite model for LC3B-ATG4b binding.
Article
Multidisciplinary Sciences
Megan L. Koleske, Gregory McInnes, Julia E. H. Brown, Neil Thomas, Keino Hutchinson, Marcus Y. Chin, Antoine Koehl, Michelle R. Arkin, Avner Schlessinger, Renata C. Gallagher, Yun S. Song, Russ B. Altman, Kathleen M. Giacomini
Summary: This study investigated the impact of variants in the SLC22A5 gene on the function of the carnitine transporter protein OCTN2 and created a predictive model. The results showed that most variants reduced carnitine transport, with some severely impairing function by at least 80%. Additionally, the study identified a major mechanism causing the loss of OCTN2 function.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Ziwen Jiang, Yu-Hsuan Kuo, Michelle R. Arkin
Summary: Autophagy is a crucial process for the degradation of large cellular contents, and impaired autophagy can lead to pathological aggregation. This study developed a novel method for targeted degradation of protein aggregates and organelles in mammalian cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Julian R. Braxton, Chad R. Altobelli, Maxwell R. Tucker, Eric Tse, Aye C. Thwin, Michelle R. Arkin, Daniel R. Southworth
Summary: This study reports the structures of p97 protein bound to the UBXD1 adaptor and identifies UBXD1 as a potent ATPase inhibitor of p97. The structures, mutagenesis, and comparisons with other adaptors reveal how UBXD1 regulates the ATPase activity and structure of p97.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Marcus Y. Chin, Jether Amos Espinosa, Grace Pohan, Sarine Markossian, Michelle R. Arkin
Summary: Organelles play crucial roles in sustaining life and their dysfunction can lead to various diseases. The development of specifically targeted fluorescent probes is essential for accelerating drug discovery. Exploring organelle-specific morphology and dynamics, along with high-content analysis, can stimulate further development of probes and approaches for high-throughput screening of organelles.
CELL CHEMICAL BIOLOGY
(2021)