Article
Chemistry, Medicinal
Theo Battista, Stefano Federico, Simone Brogi, Luca Pozzetti, Tuhina Khan, Stefania Butini, Anna Ramunno, Eleonora Fiorentino, Stefania Orsini, Trentina Di Muccio, Annarita Fiorillo, Cecile Exertier, Daniel Di Risola, Andrea Ilari, Giuseppe Campiani, Gianni Colotti, Sandra Gemma
Summary: Leishmania spp. is a significant public health issue, and developing better therapeutic drugs is urgently needed. This study optimized a novel class of Leishmania inhibitors through various approaches and identified potent and selective compounds that could be used for treating leishmaniasis and related diseases.
ACS INFECTIOUS DISEASES
(2022)
Review
Biochemistry & Molecular Biology
Manuel Montalban-Lopez, Thomas A. Scott, Sangeetha Ramesh, Imran R. Rahman, Auke J. van Heel, Jakob H. Viel, Vahe Bandarian, Elke Dittmann, Olga Genilloud, Yuki Goto, Maria Jose Grande Burgos, Colin Hill, Seokhee Kim, Jesko Koehnke, John A. Latham, A. James Link, Beatriz Martinez, Satish K. Nair, Yvain Nicolet, Sylvie Rebuffat, Hans-Georg Sahl, Dipti Sareen, Eric W. Schmidt, Lutz Schmitt, Konstantin Severinov, Roderich D. Suessmuth, Andrew W. Truman, Huan Wang, Jing-Ke Weng, Gilles P. van Wezel, Qi Zhang, Jin Zhong, Joern Piel, Douglas A. Mitchell, Oscar P. Kuipers, Wilfred A. van der Donk
Summary: This article reviews the research progress of ribosomally-synthesized and post-translationally modified peptides (RiPPs) as of June 2020, including the discovery of new RiPP classes, deeper understanding of the mechanisms for the installation of post-translational modifications, and the mechanisms by which enzymes recognize leader peptides. Additionally, genome mining tools and strategies for RiPP engineering are also discussed in the review.
NATURAL PRODUCT REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Rebekah N. Duffin, Liam J. Stephens, Victoria L. Blair, Lukasz Kedzierski, Philip C. Andrews
Summary: The study reveals that the new suite of organometallic complexes shows potential as selective drug candidates, but their behavior towards glutathione and trypanothione is not fully understood. At a clinically relevant pH range of 4-5, both complexes undergo rapid reduction in the presence of trypanothione or glutathione with no discernible difference. However, at a higher pH range of 6-7, they behave quite differently towards glutathione.
JOURNAL OF INORGANIC BIOCHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Maria Dolores Pineyro, Diego Arias, Adriana Parodi-Talice, Sergio Guerrero, Carlos Robello
Summary: Chagas Disease, African sleeping sickness, and leishmaniasis are neglected diseases caused by pathogenic trypanosomatid parasites, which have significant impact in poor countries. Current treatment drugs are toxic, difficult to access, and may lead to drug resistance. Inhibiting essential parasite metabolic pathways unique from the host can lead to more efficient and safe drug development.
CURRENT PHARMACEUTICAL DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Trong-Nhat Phan, Kyuho Paul Park, Diego Benitez, Marcelo A. Comini, David Shum, Joo Hwan No
Summary: Leishmaniasis is an infectious disease caused by the protozoa Leishmania, with high infection and death rates in developing countries. New drugs with improved pharmacological properties are urgently needed. Trypanothione synthetase (TryS) is a promising target for drug development against leishmaniasis.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Plant Sciences
Nicole Unterlander, Lili Mats, Laura C. McGary, Harley O. W. Gordon, Gale G. Bozzo
Summary: The degradation of flavonol rhamnosides in the rosette leaves of Arabidopsis and radish is associated with the accumulation of kaempferol 3-O-alpha-rhamnoside and kaempferol 7-O-alpha-rhamnoside in senescing leaves.
Article
Biochemistry & Molecular Biology
Arno G. Siraki
Summary: This review provides a comprehensive overview of myeloperoxidase (MPO) in biology, covering its historical background, role in disease, and drug development. It discusses the necessity and potential drawbacks of MPO activity, while also exploring enzyme structure, catalytic cycle, and methods of detection. Additionally, the review presents the presence of MPO in cell lines and its use as a biomarker for studying disease processes.
Editorial Material
Chemistry, Medicinal
Kaio M. Santiago-Silva, Priscila G. Camargo, Marcelle L. F. Bispo
Summary: Leishmaniasis is a global neglected tropical disease caused by parasitic protozoa. The existing treatment options are limited and have various drawbacks, leading to treatment challenges and the emergence of drug-resistant strains. Therefore, the development of new therapies for leishmaniasis is necessary. This review focuses on inhibiting essential targets involved in parasite growth, survival, and infectivity, such as Arginase and trypanothione synthase, and discusses recent discoveries of promising enzyme inhibitors.
MEDICINAL CHEMISTRY
(2023)
Review
Microbiology
Dan Zilberstein, Peter J. Myler
Summary: Leishmania parasites cause human leishmaniasis and cycle between hosts, utilizing sensors to adjust arginine transporter levels in response to environmental arginine concentrations.
CURRENT OPINION IN MICROBIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Amina Dzidic-Krivic, Jasna Kusturica, Emina Karahmet Sher, Nejra Selak, Nejra Osmancevic, Esma Karahmet Farhat, Farooq Sher
Summary: Gut microbiota, a unique collection of microorganisms in the gut, has become a popular area of research due to its important role in disease development and influence on drug pharmacokinetics. This review presents current knowledge of the interaction between commonly used drugs and the gut microbiota and the underlying mechanisms, as well as the impact on therapeutic efficacy and safety. These findings lay the foundation for personalized treatments, maximizing efficacy and minimizing side effects, which are major limitations in patient treatment.
DRUG METABOLISM REVIEWS
(2023)
Article
Medicine, Research & Experimental
John D. Clarke, Sabrina M. Judson, Dan-Dan Tian, Trevor O. Kirby, Rakshit S. Tanna, Adrienn Matula-Pentek, Miklos Horvath, Matthew E. Layton, John R. White, Nadja B. Cech, Kenneth E. Thummel, Jeannine S. Mccune, Danny D. Shen, Mary F. Paine
Summary: This study found that green tea had a pharmacokinetic interaction with raloxifene that was opposite to the predicted effect. The results suggested that one or more processes involved in intestinal absorption were affected. MRP3 was the only identified transporter that may contribute to the interaction. There was no evidence that green tea interrupted raloxifene enterohepatic recycling through inhibition of bacterial beta-glucuronidase activity. The existing gut microbiota may interact with green tea to influence raloxifene stool recovery.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2023)
Article
Multidisciplinary Sciences
Michael P. Andreas, Tobias W. Giessen
Summary: Researchers conducted a large-scale computational analysis to discover over 6,000 encapsulin-like systems, and proposed hypotheses about their potential biological functions, indicating that encapsulins likely evolved from HK97-type bacteriophages.
NATURE COMMUNICATIONS
(2021)
Article
Marine & Freshwater Biology
Jin Chen, Li Xu, Xue-Qing Zhang, Xue Liu, Zi-Xuan Zhang, Qiu-Mei Zhu, Jian-Yu Liu, Muhammad Omer Iqbal, Ning Ding, Chang-Lun Shao, Mei-Yan Wei, Yu-Chao Gu
Summary: Non-alcoholic steatohepatitis (NASH) is a leading cause of cirrhosis and hepatocellular carcinoma. A marine natural compound, candidusin A (CHNQD-0803), has been identified as a potent AMPK activator and a potential therapeutic candidate for NASH treatment.
MARINE LIFE SCIENCE & TECHNOLOGY
(2023)
Review
Pharmacology & Pharmacy
Hossein Omidian, Jafar Razmara, Sepideh Parvizpour, Hamed Tabrizchi, Yosef Masoudi-Sobhanzadeh, Yadollah Omidi
Summary: The life cycle of a drug starts from its discovery and ends when it is disposed. Various entities such as drug discovery companies, manufacturers, regulatory agencies, suppliers, pharmacies, patients, and healthcare providers are involved in this process. Transparency, traceability, automation, and data security play crucial roles in ensuring effective and safe transactions among all parties. However, challenges like scalability, energy consumption, regulations, standards, and complexity hinder the adoption of new technology that can fulfill these requirements. This article highlights how blockchain technology can track, accelerate, and enhance the efficiency of complex operations like pharmaceutical development.
DRUG DISCOVERY TODAY
(2023)
Article
Chemistry, Medicinal
Xiaoying Cai, Lun Wang, Yuyao Yi, Dexin Deng, Mingsong Shi, Minghai Tang, Na Li, Haoche Wei, Ruijia Zhang, Kaiyue Su, Haoyu Ye, Lijuan Chen
Summary: To improve the drug-like properties of HG-9-91-01, a series of pyrimidine-5-carboxamide derivatives were designed and synthesized through a molecular hybridization strategy. The most promising compound 8h showed good activity and selectivity on SIK1/2, excellent metabolic stability, increased in vivo exposure, and suitable plasma protein binding rate. This research indicates that compound 8h has the potential to be developed as an anti-inflammatory drug candidate.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Marcin J. Suskiewicz, Florian Zobel, Tom E. H. Ogden, Pietro Fontana, Antonio Ariza, Ji-Chun Yang, Kang Zhu, Lily Bracken, William J. Hawthorne, Dragana Ahel, David Neuhaus, Ivan Ahel
Article
Chemistry, Medicinal
Julien Pedron, Clotilde Boudot, Jean-Yves Brossas, Emilie Pinault, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Elisa Boutet-Robinet, Alexandre Destere, Antoine Tronnet, Justine Berge, Colin Bonduelle, Celine Deraeve, Genevieve Pratviel, Jean-Luc Stigliani, Luc Paris, Dominique Mazier, Sophie Corvaisier, Marc Since, Aureprimelie Malzert-Freon, Susan Wyllie, Rachel Milne, Alan H. Fairlamb, Alexis Valentin, Bertrand Courtioux, Pierre Verhaeghe
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Richard J. Wall, Sandra Carvalho, Rachel Milne, Juan A. Bueren-Calabuig, Sonia Moniz, Juan Cantizani-Perez, Lorna MacLean, Albane Kessler, Ignacio Cotillo, Lalitha Sastry, Sujatha Manthri, Stephen Patterson, Fabio Zuccotto, Stephen Thompson, Julio Martin, Maria Marco, Timothy J. Miles, Manu De Rycker, Michael G. Thomas, Alan H. Fairlamb, Ian H. Gilbert, Susan Wyllie
ACS INFECTIOUS DISEASES
(2020)
Article
Chemistry, Medicinal
Leah S. Torrie, David A. Robinson, Michael G. Thomas, Judith Hobrath, Sharon M. Shepherd, John M. Post, Eun-Jung Ko, Rafael Alves Ferreira, Claire J. Mackenzie, Karolina Wrobel, Darren P. Edwards, Ian H. Gilbert, David W. Gray, Alan H. Fairlamb, Manu De Rycker
ACS INFECTIOUS DISEASES
(2020)
Article
Chemistry, Medicinal
Cyril Fersing, Clotilde Boudot, Caroline Castera-Ducros, Emilie Pinault, Sebastien Hutter, Romain Paoli-Lombardo, Nicolas Primas, Julien Pedron, Line Seguy, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Jean-Luc Stigliani, Jean-Yves Brossas, Luc Paris, Alexis Valentin, Susan Wyllie, Alan H. Fairlamb, Elisa Boutet-Robinet, Sophie Corvaisier, Marc Since, Aurelie Malzert-Freon, Alexandre Destere, Dominique Mazier, Pascal Rathelot, Bertrand Courtioux, Nadine Azas, Pierre Verhaeghe, Patrice Vanelle
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Immunology
Felix Calderon, Alan H. Fairlamb, Mike Strange, Pauline Williams, Carl F. Nathan
Summary: The unique experiment of bringing academic and industrial scientists together to tackle infectious diseases has been successful. The Tres Cantos Open Lab Foundation has sustained progress in addressing tuberculosis, protozoal infections, and enteric bacterial diseases through extended stays of academics at a pharmaceutical company. This model, guided by independent experts, complements other public-private partnerships with similar goals.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Marion Schuller, Rachel E. Butler, Antonio Ariza, Callum Tromans-Coia, Gytis Jankevicius, Tim D. W. Claridge, Sharon L. Kendall, Shan Goh, Graham R. Stewart, Ivan Ahel
Summary: ADP-ribosyltransferases use NAD(+) to catalyze substrate ADP-ribosylation and regulate cellular pathways or contribute to bacterial pathogenicity. Recent studies have suggested nucleic acids as targets of reversible ADP-ribosylation. This research provides evidence of specific ADP-ribosylation of DNA in cells through the DarT-DarG system in bacteria, including global pathogens. The study reveals the structure and mechanism of the DarT enzyme, showing its evolution into specific DNA-modifying enzymes and its role in regulating growth through DNA ADP-ribosylation.
Editorial Material
Biotechnology & Applied Microbiology
Felix Calderon, Lluis Ballell, David Barros, Graeme Bilbe, Nicholas Cammack, Raquel Gabarro, Audra Halsey, Penny M. Heaton, Gagandeep Kang, Valerie Mizrahi, Carl Nathan, Mike E. Strange, Pauline M. Williams, Elizabeth A. Winzeler, Alan H. Fairlamb
Summary: Tres Cantos Open Lab is a collaborative initiative that integrates academic teams and GlaxoSmithKline to quickly test innovative therapeutic hypotheses for endemic infectious diseases. The overview provided here highlights the key scientific achievements of the project in its first decade.
NATURE REVIEWS DRUG DISCOVERY
(2021)
Article
Chemistry, Medicinal
Juliana da Silva Pacheco, Debora de Souza Costa, Edezio Ferreira Cunha-Junior, Valter Viana Andrade-Neto, Alan H. Fairlamb, Susan Wyllie, Marilia O. F. Goulart, Danyelle C. Santos, Thaissa L. Silva, Marina A. Alves, Paulo R. R. Costa, Ayres G. Dias, Eduardo Caio Torres-Santos
Summary: 5-nitro-furan nitrones (1) and 5-nitro-thiophene nitrones (2) were synthesized in one step and showed potent leishmanicidal activity, particularly against intracellular amastigote forms of Leishmania amazonensis and L. infantum. The redox potential of the compounds was modulated by the nitrone group, which could potentially slow the development of resistance. Oral administration of 1b in mice infected by L. infantum significantly reduced parasite load in the spleen and liver.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Multidisciplinary Sciences
Johannes Gregor Matthias Rack, Qiang Liu, Valentina Zorzini, Jim Voorneveld, Antonio Ariza, Kourosh Honarmand Ebrahimi, Julia M. Reber, Sarah C. Krassnig, Dragana Ahel, Gijsbert A. van der Marel, Aswin Mangerich, James S. O. McCullagh, Dmitri V. Filippov, Ivan Ahel
Summary: Poly(ADP-ribosyl)ation is a versatile posttranslational modification involved in regulating cellular processes. This study focuses on the mechanisms of PAR removal by PARG and ARH3, highlighting their differences in hydrolysis of linear and terminal ADP-ribose linkages.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Pietro Fontana, Sara C. Buch-Larsen, Osamu Suyari, Rebecca Smith, Marcin J. Suskiewicz, Kira Schutzenhofer, Antonio Ariza, Johannes Gregor Matthias Rack, Michael L. Nielsen, Ivan Ahel
Summary: ADP-ribosylation signalling plays a crucial role in the DNA damage response of mammals, and its mechanism in fruit flies has been established using a multidisciplinary approach. Ser-ADPr is the major form of ADP-ribosylation in the DNA damage response of Drosophila melanogaster, and its formation depends on the dParp1:dHpf1 complex. The findings suggest that fruit flies are valuable model organisms to study the physiological role of Ser-ADPr signalling.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Christopher J. Carnie, Lucy Armstrong, Marek Sebesta, Antonio Ariza, Xiaomeng Wang, Emily Graham, Kang Zhu, Dragana Ahel
Summary: This study identifies ERCC6L2 as a key regulator of centromere inheritance and replication, as well as replication of genomic repeats and non-canonical DNA structures. ERCC6L2 interacts with the DNA-clamp PCNA and restricts DNA end resection. The findings provide a mechanistic model for the diverse functions of ERCC6L2 in DNA repair and replication, and offer molecular insights into its role in human diseases.
Correction
Multidisciplinary Sciences
Susan Wyllie, Michael Thomas, Stephen Patterson, Sabrinia Crouch, Manu De Rycker, Rhiannon Lowe, Stephanie Gresham, Michael D. Urbaniak, Thomas D. Otto, Laste Stojanovski, Frederick R. C. Simeons, Sujatha Manthri, Lorna M. MacLean, Fabio Zuccotto, Nadine Homeyer, Hannah Pflaumer, Markus Boesche, Lalitha Sastry, Paul Connolly, Sebastian Albrecht, Matt Berriman, Gerard Drewes, David W. Gray, Sonja Ghidelli-Disse, Susan Dixon, Jose M. Fiandor, Paul G. Wyatt, Michael A. J. Ferguson, Alan H. Fairlamb, Timothy J. Miles, Kevin D. Read, Ian H. Gilbert
Article
Biochemistry & Molecular Biology
Luciana S. Paradela, Richard J. Wall, Sandra Carvalho, Giulia Chemi, Victoriano Corpas-Lopez, Eoin Moynihan, Davide Bello, Stephen Patterson, Maria Lucia S. Guther, Alan H. Fairlamb, Michael A. J. Ferguson, Fabio Zuccotto, Julio Martin, Ian H. Gilbert, Susan Wyllie
Summary: A benzothiophene compound with activity against Leishmania donovani was found, with oxidosqualene cyclase (OSC) identified as its target. The amplification of the OSC gene was associated with resistance to the compound, and introduction of an ectopic copy of the gene reduced susceptibility. Biochemical analyses showed substrate accumulation and product depletion in cells treated with the compound, confirming direct binding of the compound to OSC.
CELL CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Cyril Fersing, Clotilde Boudot, Romain Paoli-Lombardo, Nicolas Primas, Emilie Pinault, Sebastien Hutter, Caroline Castera-Ducros, Youssef Kabri, Julien Pedron, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Jean-Luc Stigliani, Alexis Valentin, Amaya Azqueta, Damian Muruzabal, Alexandre Destere, Susan Wyllie, Alan H. Fairlamb, Sophie Corvaisier, Marc Since, Aurelie Malzert-Freon, Carole Di Giorgio, Pascal Rathelot, Nadine Azas, Bertrand Courtioux, Patrice Vanelle, Pierre Verhaeghe
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2020)
