Article
Chemistry, Medicinal
Karolina Vankova, Dianne T. Keough, Dana Hockova, Luke W. Guddat, Zlatko Janeba
Summary: Twelve N2'-branched acyclic nucleoside phosphonates and bisphosphonates were synthesized as potential inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). The compounds showed low to modest selectivity for the parasite enzyme over human HGPRT. The effect of different chemical groups/linkers attached to N2' atom on inhibition constants and selectivity was discussed.
Article
Chemistry, Medicinal
Jan Frydrych, Dianne T. Keough, Marina Chavchich, Jye Travis, Martin Dracinsky, Michael D. Edstein, Luke W. Guddat, Dana Hockova, Zlatko Janeba
Summary: A series of novel nucleotide analogues were designed, synthesized, and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT, and human HGPRT, exhibiting a broad range of antimalarial activity. Among them, the bisphosphoramidate prodrug 13a showed good selectivity and low cytotoxicity against the chloroquine-resistant P. falciparum W2 strain.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Tomas Klejch, Dianne T. Keough, Gordon King, Eva Dolezelova, Michal Cesnek, Milos Budesinsky, Alena Zikova, Zlatko Janeba, Luke W. Guddat, Dana Hockova
Summary: Pathogens rely on host cells to salvage purines and nucleosides for nucleotide synthesis. Researchers synthesized 16 novel acyclic nucleoside phosphonates and found that bisphosphonate (S,S)-48 is the most potent inhibitor of Plasmodium, Trypanosoma, and human enzymes, with different conformational binding to parasite and human enzymes.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Eva Dolezelova, Tomas Klejch, Petr Spacek, Martina Slapnickova, Luke Guddat, Dana Hockova, Alena Zikova
Summary: Medically important unicellular protozoans rely on the purine salvage pathway (PSP) as they cannot synthesize purines de novo. A Trypanosoma brucei enzyme involved in the salvage of adenine, adenine phosphoribosyl transferase (APRT), was characterized, and potential inhibitors were designed. These inhibitors showed anti-trypanosomal activity, suggesting they can be further explored for their actual target(s) in T. brucei.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Medicinal
Karolina Vankova, Eva Dolezelova, Eva Tloustova, Dana Hockova, Alena Zikova, Zlatko Janeba
Summary: A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) were synthesized using the optimized Suzuki cross-coupling reaction. Compound 14h, which contains two phosphonate moieties, showed potent anti-trypanosomal activity and low micromolar cytotoxicity against leukemia and/or cancer cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Filip Kalcic, Jan Frydrych, Eva Dolezelova, Martina Slapnickova, Petr Pachl, Lenka Postova Slavetinska, Martin Dracinsky, Dana Hockova, Alena Zikova, Zlatko Janeba
Summary: A study identified novel ANPs as inhibitors of key enzymes in the purine salvage pathway in certain pathogens, with two ANPs showing potent inhibition of Trypanosoma brucei adenine PRT activity. The configuration at the C1' chiral center strongly influenced their activity, with (R)-enantiomers being more potent than (S)enantiomers. These findings provide important tools for further research on purine metabolism in various parasites.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Lanxin Zhang, G. S. M. Kiruba, Jeehiun K. Lee
Summary: In this study, the gas-phase acidity and proton affinity of nucleobases that act as substrates for Pf HG-(X)-PRT were investigated using computational and experimental methods. These previously unmeasured thermodynamic values provide experimental data to validate theoretical results. The findings can offer insights into the mechanism of Pf HG-(X)-PRT and suggest possible kinetic isotope studies to distinguish between mechanisms.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Danielle Figueredo da Silva, Jessica Lima de Souza, Diego Mota da Costa Jr, David Bacelar Costa, Paulo Otavio Lourenco Moreira, Amanda Luisa da Fonseca, Fernando de Pilla Varotti, Jorddy Neves Cruz, Cleydson Breno Rodrigues dos Santos, Clayton Queiroz Alves, Franco Henrique Andrade Leite, Hugo Neves Brandao
Summary: This study aimed to evaluate the antiplasmodial activity of auraptene and poligalen against a chloroquine-resistant strain of Plasmodium falciparum. The results showed that auraptene and poligalen exhibited antiplasmodial activity against Plasmodium falciparum, with high selectivity indexes. Molecular dynamics studies demonstrated the stability of coumarins at the binding site and favorable binding energies.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Petra Brehova, Ema Chaloupecka, Michal Cesnek, Jan Skacel, Martin Dracinsky, Eva Tloustova, Helena Mertlikova-Kaiserova, Monica P. Soto-Velasquez, Val J. Watts, Zlatko Janeba
Summary: A series of novel acyclic nucleoside phosphonates (ANPs) were synthesized and evaluated as potential adenylate cyclase inhibitors, showing promising inhibitory effects on various toxins and enzymes. Some compounds were identified as potential leads for the treatment of human inflammatory and neuropathic pain.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Isabell Berneburg, Satyamaheshwar Peddibhotla, Kim C. Heimsch, Kristina Haeussler, Patrick Maloney, Palak Gosalia, Janina Preuss, Mahsa Rahbari, Oleksii Skorokhod, Elena Valente, Daniela Ulliers, Luigi Felice Simula, Kathrin Buchholz, Michael P. Hedrick, Paul Hershberger, Thomas D. Y. Chung, Michael R. Jackson, Evelin Schwarzer, Stefan Rahlfs, Lars Bode, Katja Becker, Anthony B. Pinkerton
Summary: This study reports on a highly selective PfGluPho inhibitor, SBI-0797750, which shows potent activity against Plasmodium parasites. The compound disturbs the redox potential and H2O2 homeostasis of the parasites, without harming red blood cell integrity and phagocytosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Cai Lin, Izet Karalic, An Matheeussen, Pim-Bart Feijens, Fabian Hulpia, Louis Maes, Guy Caljon, Serge Van Calenbergh
Summary: Leishmaniasis is a disease that causes high mortality and morbidity in tropical and subtropical regions of Africa, Asia, the Americas, and southern Europe. Limited resources are allocated for antileishmanial drug discovery. A study found that by interfering with the purine salvage pathway, a purine analogue can selectively hinder the growth and survival of the Leishmania parasite.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Alice Pomeislova, Miroslav Otmar, Petra Rubesova, Jakub Benysek, Marika Matousova, Helena Mertlikova-Kaiserova, Radek Pohl, Lenka Postova Slavetinska, Karel Pomeisl, Marcela Krecmerova
Summary: A series of novel 1,2,4-thiadiazol-3(2H)-ones were synthesized and explored as potential inhibitors of cysteine-dependent enzymes - human cathepsin K and glycogen synthase kinase 3 beta. Some compounds exhibited inhibitory activity toward both enzymes in the low micromolar range, with some showing similar inhibitory potency to tideglusib towards GSK-3 beta but with more favorable toxicity profile.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Theodoric A. Mattes, Lahiru Malalasekara, Jorge C. Escalante-Semerena
Summary: The study reports an enzyme from Geobacillus kaustophilus that converts alpha-R to alpha-R-phosphate and exhibits specificity for certain alpha-N-linked ribosides. The enzyme does not phosphorylate beta-N-linked glycosides and alpha-adenosine is unable to support growth under certain conditions, despite being phosphorylated by the enzyme in vitro.
Article
Biochemistry & Molecular Biology
Yacoba V. T. Minnow, Kajitha Suthagar, Keith Clinch, Rodrigo G. Ducati, Agnidipta Ghosh, Joshua N. Buckler, Rajesh K. Harijan, Sean M. Cahill, Peter C. Tyler, Vern L. Schramm
Summary: Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT) is an essential enzyme for the salvage pathway of hypoxanthine into parasite purine nucleotides. In this study, transition state analogue inhibitors of PfHGXPRT were characterized using kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound 1, which is an acyclic ribocation phosphonate mimic linked to 9-deazaguanine, showed a kinetic Ki of 0.5 nM. Isothermal titration calorimetry experiments revealed enthalpically driven binding of compound 1 to PfHGXPRT with negative cooperativity. Crystal structures of the inhibitor bound to the enzyme provided insights into the hydrogen bond and ionic contacts involved in the binding process. The dynamics of ribosyl transfer from 5-phospho-alpha-D-ribosyl 1-pyrophosphate (PRPP) to hypoxanthine were investigated using 18O isotope exchange, which showed that rotational constraints and short transition state lifetimes prevented positional isotope exchange. The thermodynamic analysis of the transition state analogue and magnesium pyrophosphate binding indicated random and cooperative binding to PfHGXPRT, suggesting a different mechanism from the previously reported substrate kinetics.
ACS CHEMICAL BIOLOGY
(2022)
Article
Public, Environmental & Occupational Health
Oum Kelthoum Mamadou Djigo, Nicolas Gomez, Mohamed Salem Ould Ahmedou Salem, Leonardo Basco, Ali Ould Mohamed Salem Boukhary, Sebastien Briolant
Summary: The study aimed to evaluate the performance of multiplex allele-specific polymerase chain reaction (PCR) in Mauritanian blood samples. The African-type Diaplex CTM G6PD genotyping kit showed a sensitivity of 100% and specificity of 99% in identifying mutations associated with G6PD A- genotypes. Despite limitations in the PCR protocol and predicting enzyme levels in heterozygous females, the kit proved to be valuable in screening male subjects and for research purposes in resource-limited countries.
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
(2023)
Article
Microbiology
Laura Seldeslachts, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Lauren Van der Sloten, Stephanie Humblet-Baron, Lieve Naesens, Katrien Lagrou, Erik Verbeken, Joost Wauters, Greetje Vande Velde
Summary: The study found that baloxavir marboxil has a therapeutic effect on influenza-associated pulmonary aspergillosis, improving body weight, survival, and viral clearance in a mouse model. It also reduces lung lesions and fungal burden, suggesting that baloxavir marboxil can mitigate severe influenza and decrease the risk of lethal invasive Aspergillus superinfection.
Review
Chemistry, Multidisciplinary
Marcela Krecmerova
Article
Physics, Multidisciplinary
Gary J. Cowin, Karine Mardon, Zachary H. Houston, Rajiv Bhalla, Damion H. R. Stimson, Kristofer J. Thurecht, Ian M. Brereton
Summary: The study utilized dynamic gadolinium-enhanced magnetic resonance - positron emission tomography to independently evaluate vascular delivery and blood brain barrier integrity in brain tumors. It also observed the dynamic changes of therapeutic agents. This method can provide important information on the alterations of therapeutic agent delivery and uptake.
FRONTIERS IN PHYSICS
(2022)
Article
Chemistry, Medicinal
Gokce Cihan-Ustundag, Cigdem Acar, Lieve Naesens, Gonca Erkose-Genc, Dilek Satana
Summary: We synthesized a novel series of hybrid spirothiazolidinone derivatives and evaluated their antiviral and antitubercular activities. Some of these compounds showed specific antiviral activity against the influenza A/H3N2 virus, with the most active compound being 3a with an antiviral EC50 value of 5.2μM. In addition, some compounds also exhibited inhibitory activity against Mycobacterium tuberculosis.
ARCHIV DER PHARMAZIE
(2022)
Article
Microbiology
Annelies Stevaert, Ria Van Berwaer, Cato Mestdagh, Julie Vandeput, Els Vanstreels, Valerie Raeymaekers, Manon Laporte, Lieve Naesens
Summary: The S2' motif in the SARS-CoV-2 spike protein plays a crucial role in spike activation, with TMPRSS2 showing more tolerance to variations than TMPRSS13. This insight will help in estimating the impact of S2' motif changes in new variants.
Article
Pharmacology & Pharmacy
Bert Vanmechelen, Joren Stroobants, Winston Chiu, Lieve Naesens, Joost Schepers, Kurt Vermeire, Piet Maes
Summary: This study successfully achieved biological containment of Marburg virus, demonstrating its feasibility for other filoviruses. By using genetic engineering and specific cell lines, the virus can be handled safely in lower biosafety settings.
ANTIVIRAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Miklos Bege, Alexandra Kiss, Ilona Bereczki, Jan Hodek, Lenke Polyak, Gabor Szeman-Nagy, Lieve Naesens, Jan Weber, Aniko Borbas
Summary: In this study, d-arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were synthesized by photoinitiated, radical-mediated hydrothiolation reactions. Some of these compounds exhibited selective cytotoxicity against tumor cells and also showed antiviral activity against SARS-CoV-2 and/or HCoV-229E.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Ilona Bereczki, Vladimir Vimberg, Eszter Lorincz, Henrietta Papp, Lajos Nagy, Sandor Keki, Gyula Batta, Ana Mitrovic, Janko Kos, Aron Zsigmond, Istvan Hajdu, Zsolt Lorincz, David Bajusz, Laszlo Petri, Jan Hodek, Ferenc Jakab, Gyorgy M. Keseru, Jan Weber, Lieve Naesens, Pal Herczegh, Aniko Borbas
Summary: Patients infected with SARS-CoV-2 are at risk of co-infection with Gram-positive bacteria, which greatly affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be valuable in this context. The researchers synthesized and evaluated seven derivatives of teicoplanin, a glycopeptide antibiotic, with hydrophobic or superbasic side chains. Except for one derivative, all teicoplanin derivatives effectively inhibited SARS-CoV-2 replication in VeroE6 cells. Some of these derivatives also showed activity against HCoV-229E, a human coronavirus, in human Calu-3 cells. The study revealed that the teicoplanin derivatives efficiently prevented the entry of SARS-CoV-2 into cells through both endosomal and surface entry routes. Moreover, these derivatives exhibited good to excellent activity against Gram-positive bacteria resistant to glycopeptide antibiotics.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Medicinal
Sonia De Castro, Annelies Stevaert, Miguel Maldonado, Adrien Delpal, Julie Vandeput, Benjamin Van Loy, Cecilia Eydoux, Jean-Claude Guillemot, Etienne Decroly, Federico Gago, Bruno Canard, Maria-Jose Camarasa, Sonsoles Velazquez, Lieve Naesens
Summary: There is a need for novel antiviral concepts to control SARS-CoV-2 infection. A class of 1,4,4-trisubstituted piperidines have shown promising anti-coronavirus activity. Several analogues were synthesized and evaluated, and four molecules demonstrated micromolar activity against SARS-CoV-2. These compounds were found to inhibit the main protease (M-pro) of SARS-CoV-2, suggesting they could serve as non-covalent inhibitors for further development.
Article
Virology
Annelies Stevaert, Elisabetta Groaz, Lieve Naesens
Summary: The COVID-19 pandemic has accelerated the development of nucleoside analogs for treating respiratory virus infections. Remdesivir is the first authorized compound, and three other nucleoside analogs are in the pipeline. This article summarizes the current knowledge on their clinical efficacy and mentions trials for influenza and respiratory syncytial virus. Furthermore, it outlines how nucleoside analogs interact with respiratory virus polymerases to cause lethal virus mutagenesis or disturbance of viral RNA synthesis.
CURRENT OPINION IN VIROLOGY
(2022)
Article
Agriculture, Multidisciplinary
Yan Cheng, Thierry Lonhienne, Mario D. Garcia, Craig M. Williams, Gerard Schenk, Luke W. Guddat
Summary: Amidosulfuron (AS), a commercial sulfonylurea herbicide, effectively targets dicot broadleaf weeds by inhibiting acetohydroxyacid synthase (AHAS) in the plants. The crystal structure analysis shows that AS lacks a second aromatic ring compared to other AHAS-inhibiting herbicides, but still exhibits potent herbicidal activity through accumulative inhibition. This study highlights the importance of accumulative inhibition in designing effective herbicides targeting plant AHAS.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Evelien Vanderlinden, Arnaud Boonen, Sam Noppen, Geert Schoofs, Maya Imbrechts, Nick Geukens, Robert Snoeck, Annelies Stevaert, Lieve Naesens, Graciela Andrei, Dominique Schols
Summary: PRO-2000, a sulfonated polyanionic compound, has anti-SARS-CoV-2 activity by blocking the entry pathway and inhibiting the binding of the S protein to its receptor. It can potentially inhibit a broad range of SARS-CoV-2 variants.
ANTIVIRAL RESEARCH
(2023)
Article
Chemistry, Medicinal
Rui Wang, Annelies Stevaert, Tien Nguyen Truong, Qifei Li, Besir Krasniqi, Benjamin Van Loy, Arnout Voet, Lieve Naesens, Wim Dehaen
Summary: The study investigates the structure-activity relationship of novel coronavirus inhibitors and identifies a class of 1,2,3-triazolo fused triterpenoid compounds with strong antiviral activity against HCoV-229E.
ARCHIV DER PHARMAZIE
(2023)
Article
Biochemistry & Molecular Biology
Pavel Kraina, Michal Cesnek, Eva Tloustova, Helena Mertlikova-Kaiserova, Camryn J. Fulton, Emily K. Davidson, Brenton P. Smith, Val J. Watts, Zlatko Janeba
Summary: A series of novel 7-substituted 7-deazaadefovir analogues were synthesized, and 12 of them were found to be single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin. Compound 14 was identified as a potent, non-toxic, and selective mAC2 inhibitor.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Meeting Abstract
Cardiac & Cardiovascular Systems
J. Kaes, E. Vanhulle, L. Seldeslachts, C. Hooft, H. Beeckmans, X. Jin, P. Kerckhof, J. Van Slambrouck, D. Van Raemelonck, G. Vande Velde, L. Naesens, D. Schols, L. J. Ceulemans, R. Vos, K. Vertneire, B. M. Vanaudenaerde
JOURNAL OF HEART AND LUNG TRANSPLANTATION
(2023)
