Article
Chemistry, Medicinal
Natalie Losada, Francesc X. Ruiz, Francesca Curreli, Kevin Gruber, Alyssa Pilch, Kalyan Das, Asim K. Debnath, Eddy Arnold
Summary: This study focuses on compounds (NBD derivatives) originally developed to bind to HIV-1 gp120, some of which inhibit RT. Crystal structures of three NBD compounds in complex with HIV-1 RT have been determined, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Two lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity and low cytotoxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Giavana R. Prucha, Sean Henry, Klarissa Hollander, Zachary J. Carter, Krasimir A. Spasov, William L. Jorgensen, Karen S. Anderson
Summary: This study reports the synthesis of 34 compounds that covalently inhibit reverse transcriptase to overcome the issue of resistance to non-nucleoside reverse transcriptase inhibitors. Two of these inhibitors demonstrate biochemical, structural, enzyme kinetic, mass spectrometry, and antiviral activity against HIV-1.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Matthew Weichseldorfer, Marvin Reitz, Olga S. Latinovic
Summary: Combined antiretroviral therapy (cART) is widely recommended for controlling HIV-1 replication and improving the quality of life of infected individuals. However, latent infected cells remain a major barrier to treatment efficacy in the long term.
Article
Cell Biology
Carl J. Balibar, Daniel J. Klein, Beata Zamlynny, Tracy L. Diamond, Zhiyu Fang, Carol A. Cheney, Jan Kristoff, Meiqing Lu, Marina Bukhtiyarova, Yangsi Ou, Min Xu, Lei Ba, Steven S. Carroll, Abdellatif El Marrouni, John F. Fay, Ashley Forster, Shih Lin Goh, Meigang Gu, Daniel Krosky, Daniel I. S. Rosenbloom, Payal Sheth, Deping Wang, Guoxin Wu, Matthias Zebisch, Tian Zhao, Paul Zuck, Jay Grobler, Daria J. Hazuda, Bonnie J. Howell, Antonella Converso
Summary: Antiretroviral therapy can inhibit HIV-1 replication but cannot cure the infection due to the persistence of a reservoir in the host genome. Reduction of this reservoir is important for HIV-1 cure. Some nonnucleoside reverse transcriptase inhibitors have shown selective cytotoxicity against HIV-1 in vitro, but their concentrations required are much higher than approved dosages. By focusing on this secondary activity, researchers have discovered bifunctional compounds called targeted activators of cell kill (TACK) that can kill HIV-1-infected cells at clinically achievable concentrations. These TACK molecules bind to the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators, promoting dimerization and premature intracellular viral protease activation, leading to death of HIV-1(+) cells. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4(+) T cells, providing a potential immune-independent clearance strategy.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Virology
Maria E. Cilento, Xin Wen, Aaron B. Reeve, Obiaara B. Ukah, Alexa A. Snyder, Ciro M. Carrillo, Cole P. Smith, Kristin Edwards, Claudia C. Wahoski, Deborah R. Kitzler, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Philip R. Tedbury, Stefan G. Sarafianos
Summary: TDF and ISL are highly potent nucleoside reverse transcriptase inhibitors with different resistance profiles. This study found that ISL is sensitive to the K65R mutation, while TDF is sensitive to the M184V mutation. The sensitivity to these drugs also varies among different HIV subtypes, and the S68G polymorphism may enhance the fitness of drug-resistant mutants in certain genetic backgrounds.
Article
Biochemistry & Molecular Biology
Kamil Latka, Marek Bajda
Summary: In this study, the structure and binding sites of glycine transporters were investigated using crystal structures and simulation methods. The results reveal the important roles of certain amino acids in selective ligand binding, providing insights for the future design of ideal glycine transporter inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biotechnology & Applied Microbiology
Ruofan Wang, Ashton T. Belew, Vasudevan Achuthan, Najib El Sayed, Jeffrey J. DeStefano
Summary: Recent analyses have shown that certain subtypes of HIV-1 have higher fidelity in low Mg2+ conditions, while some RTs demonstrate higher fidelity at physiological Mg2+ levels. Sequencing methods have revealed the mutation profiles of HIV-1 RT under different Mg2+ concentrations.
JOURNAL OF GENERAL VIROLOGY
(2021)
Article
Microbiology
Paul L. Boyer, Catherine A. Rehm, Michael C. Sneller, JoAnn Mican, Margaret R. Caplan, Robin Dewar, Andrea L. Ferris, Patrick Clark, Adam Johnson, Frank Maldarelli, Stephen H. Hughes
Summary: Resistance to anti-HIV drugs is a problem, especially with the expansion of combination antiretroviral therapy. This study analyzed reverse transcriptase variants in an individual undergoing treatment and found that some mutations still made the virus susceptible to drugs.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Xiangyi Jiang, Boshi Huang, Waleed A. Zalloum, Chin-Ho Chen, Xiangkai Ji, Zhen Gao, Jiaojiao Dai, Minghui Xie, Dongwei Kang, Erik De Clercq, Christophe Pannecouque, Xinyong Liu, Peng Zhan
Summary: Novel diarypyrimidine derivatives were designed based on previously reported HIV-1 NNRTIs BH-11c and XJ-10c to improve antiresistance and drug-like profiles. Compound 12g showed the highest inhibitory activity against wild-type and NNRTI-resistant HIV-1 strains, with EC50 values ranging from 0.024 to 0.0010 μM. Its improved antiresistance profile compared to ETR was explained by MD simulation study and it also showed improved water solubility and other drug-like properties. Compound 12g exhibited promising pharmacokinetics parameters and could be a potential lead compound for new antiretroviral drug development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Kolin M. Clark, Josh G. Kim, Qiankun Wang, Hongbo Gao, Rachel M. Presti, Liang Shan
Summary: The sensitization of the CARD8 inflammasome to non-nucleoside reverse transcriptase inhibitors (NNRTIs) can be achieved through chemical inhibition of the negative regulator DPP9. The DPP9 inhibitor Val-boroPro (VbP) can kill HIV-1-infected cells without NNRTIs and synergize with NNRTIs to promote clearance of infected cells. This offers a promising strategy for enhancing NNRTI efficacy in eliminating HIV-1 reservoirs.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Roberto Arrigoni, Luigi Santacroce, Andrea Ballini, Luigi Leonardo Palese
Summary: The availability of drugs capable of blocking microorganism replication is a major accomplishment in medicine, but the increasing number of resistant strains poses a significant challenge for infectious disease treatment. Therefore, the search for new potential ligands for pathogens' life cycle is a crucial research area today.
Article
Chemistry, Medicinal
Yanying Sun, Zhenzhen Zhou, Da Feng, Lanlan Jing, Fabao Zhao, Zhao Wang, Tao Zhang, Hao Lin, Hao Song, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu, Dongwei Kang
Summary: A series of novel diarylpyrimidine derivatives were generated using a cocrystal structure-based drug design strategy to discover new HIV-1 NNRTIs with increased drug resistance profiles and improved PK properties. Among them, compound 36a exhibited outstanding antiviral activity and higher binding affinity to HIV-1 RT. Molecular docking and simulation were performed to rationalize the design and improved drug resistance. Compound 36a·HCl showed favorable PK and safety properties, suggesting it as a potential drug candidate for anti-HIV-1 therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Parisa Sistani, Gholamreza Dehghan, Leila Sadeghi
Summary: The study revealed that FC inhibits HIV-1 RT activity through a mixed inhibition mechanism and affects its structure and function through static quenching mechanism. The interaction between FC and HIV-1 RT is mainly influenced by hydrogen bonding and van der Waals forces, with high affinity observed.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Mahta Mansouri, Shawn Rumrill, Shane Dawson, Adam Johnson, Jo-Anne Pinson, Menachem J. Gunzburg, Catherine F. Latham, Nicholas Barlow, George W. Mbogo, Paula Ellenberg, Stephen J. Headey, Nicolas Sluis-Cremer, David Tyssen, Joseph D. Bauman, Francesc X. Ruiz, Eddy Arnold, David K. Chalmers, Gilda Tachedjian
Summary: Human immunodeficiency virus type I (HIV-1) is a major global health burden, and the emergence of drug-resistance mutations necessitates the development of novel drugs. In this study, a fragment-based drug discovery approach was used to optimize a hit fragment (compound B-1) that targets the viral protein reverse transcriptase (RT) in a novel site. Different compound series were synthesized and evaluated for their RT binding and inhibition, leading to the identification of a lead compound with promising inhibitory activity. This study offers a starting point for the development of novel dual inhibitors targeting the NNRTI-binding pocket and an adjacent site.
Article
Chemistry, Medicinal
Joseph A. Ippolito, Haichan Niu, Nicole Bertoletti, Zachary J. Carter, Shengyan Jin, Krasimir A. Spasov, Jose A. Cisneros, Margarita Valhondo, Kara J. Cutrona, Karen S. Anderson, William L. Jorgensen
Summary: Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead demonstrate potent inhibition, with IC50 values for in vitro inhibition of WT RT and EC50 values for cytopathic protection of HIV-1-infected human T-cells in the range of 5-320 nM.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Organic
Estefania Capel, Marta Rodriguez-Rodriguez, Uxue Uria, Manuel Pedron, Tomas Tejero, Jose L. Vicario, Pedro Merino
Summary: The catalyzed desymmetrizative ring expansion of alkenylcyclobutanols promoted by halofunctionalization of the alkene moiety with N-bromosuccinimide has been experimentally and computationally studied. The reaction is found to yield highly enantioenriched cyclopentanones with two all-carbon quaternary stereocenters, and the mechanistic studies suggest the formation of an ion pair leading to a complex with only a unit of phosphoric acid. Computational studies reveal the reaction as a highly asynchronous concerted process taking place as one kinetic step but in two stages, with no intermediates present in the reaction as energy minima.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Robert Lassfolk, Manuel Pedron, Tomas Tejero, Pedro Merino, Johan Warna, Reko Leino
Summary: Acyl group migration plays a significant role in the synthesis, isolation, manipulation and purification of acylated organic compounds containing free hydroxyl groups, especially carbohydrates. Our study reveals that the anomeric configuration in monosaccharides, along with the relative configurations of other hydroxyl groups and the properties of the migrating acyl group, greatly influence the migration rate.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Physical
Consuelo Celesti, Teresa Gervasi, Nicola Cicero, Salvatore Vincenzo Giofre, Claudia Espro, Elpida Piperopoulos, Bartolo Gabriele, Raffaella Mancuso, Giovanna Lo Vecchio, Daniela Iannazzo
Summary: This study investigated the possibility of enhancing the antibacterial properties of titanium implants by covalently inserting bioactive ammonium salts onto the surface of titanium substrates. The chemically modified samples showed good resistance against bacterial adhesion, particularly when containing long alkyl chains. The results underscored the importance of chemical functionalization in improving the antimicrobial activity of metal surfaces.
Editorial Material
Oncology
Claudia Matteucci, Emanuela Balestrieri, Tara Patricia Hurst, Gkikas Magiorkinis, Reiner Strick
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Gaetana Costanza, Pierpaolo Paba, Marco Ciotti, Domenico Ombres, Stefano Di Carlo, Fabbio Marcuccilli, Ada Bertoli, Loide Di Traglia, Marcello Mozzani, Lucia Piredda, Vita Petrone, Marialaura Fanelli, Carla Paganelli, Barbara Cortese, Emanuela Balestrieri, Sergio Bernardini, Massimo Andreoni, Claudia Matteucci, Antonella Minutolo, Sandro Grelli
Summary: This study provides a dynamic picture of the epidemiological curve of common respiratory viruses during the two-year pandemic, showing that SARS-CoV-2 has a preferential tropism for the respiratory tract without co-existing with other viruses. This may be attributed to the use of masks, social isolation, and the presence of specific respiratory receptors.
Article
Biology
Francesca Marino-Merlo, Valeria Stefanizzi, Agnese Ragno, Lucia Piredda, Sandro Grelli, Beatrice Macchi, Antonio Mastino
Summary: The study developed a real-time reverse transcriptase quantitative PCR (RT-qPCR) assay to assess very low levels of HIV-1 RT activity based on previous laboratory experience. A synthetic RNA was used as a template for reverse transcription into cDNA by HIV-1 RT, and different variables were tested to optimize the assay. The optimized gD-RNA-synt-based RT assay demonstrated high sensitivity, allowing for the detection of specific cDNA reverse transcription even in the presence of 1 x 10(-9) U HIV RT. This constructed RT-qPCR assay shows promise in accurately assessing very low HIV-1 RT activity.
Review
Microbiology
Marialaura Fanelli, Vita Petrone, Margherita Buonifacio, Elisabetta Delibato, Emanuela Balestrieri, Sandro Grelli, Antonella Minutolo, Claudia Matteucci
Summary: The presence of ACE2 receptor in various tissues allows the COVID-19 disease to affect multiple organs. SARS-CoV-2 infects different cell types, leading to cytokine storm and immune system imbalance. Changes in microbial diversity and dysbiosis persist in COVID-19 patients. Understanding the role of the immune system during infection is crucial for addressing chronic multisystem dysfunction related to COVID-19.
Article
Biochemistry & Molecular Biology
Francesca Marino-Merlo, Anusha Klett, Emanuela Papaianni, Selene Francesca Anna Drago, Beatrice Macchi, Maria Gabriela Rincon, Federica Andreola, Annalucia Serafino, Sandro Grelli, Antonio Mastino, Christoph Borner
Summary: This study investigates the molecular mechanisms of apoptosis induced by HSV-1, showing that caspase-8 plays a crucial role in both HSV-1-induced apoptosis and viral particle release through autophagic regulation.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Biochemistry & Molecular Biology
Chiara Cipriani, Anna Maria Tartaglione, Martina Giudice, Erica D'Avorio, Vita Petrone, Nicola Toschi, Flavia Chiarotti, Martino Tony Miele, Gemma Calamandrei, Enrico Garaci, Claudia Matteucci, Paola Sinibaldi-Vallebona, Laura Ricceri, Emanuela Balestrieri
Summary: Maternal infections during pregnancy and the consequent maternal immune activation (MIA) are major risk factors for autism spectrum disorder (ASD). Preclinical models have shown that MIA can lead to ASD-like behavioral abnormalities and altered neuroinflammatory profiles. Abnormal expression of endogenous retroviruses (ERVs) has also been identified in neurodevelopmental disorders and is correlated with disease severity. This study aimed to evaluate the transcriptional profile of ERVs and inflammatory mediators in mouse offspring prenatally exposed to Poly I:C, a synthetic double-stranded RNA molecule that mimics viral maternal infection. The findings support the tissue specificity of ERV and ERV-related transcriptional profiles in MIA mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Virology
Chiara Cipriani, Martina Giudice, Vita Petrone, Marialaura Fanelli, Antonella Minutolo, Martino T. T. Miele, Nicola Toschi, Christian Maracchioni, Martina Siracusano, Arianna Benvenuto, Antonella Coniglio, Paolo Curatolo, Luigi Mazzone, Grelli Sandro, Enrico Garaci, Paola Sinibaldi-Vallebona, Claudia Matteucci, Emanuela Balestrieri
Summary: Our study shows that autistic children and their mothers have an intrinsic responsiveness to in vitro microenvironmental changes in expressing HERVs and pro-inflammatory cytokines. The antiretroviral drug Efavirenz can restore the expression of specific HERV families and reduce pro-inflammatory cytokines expression.
Article
Biochemistry & Molecular Biology
Valeria Stefanizzi, Antonella Minutolo, Elena Valletta, Martina Carlini, Franca M. M. Cordero, Anna Ranzenigo, Salvatore Pasquale Prete, Daniel Oscar Cicero, Erica Pitti, Greta Petrella, Claudia Matteucci, Francesca Marino-Merlo, Antonio Mastino, Beatrice Macchi
Summary: Metal-derived platinum complexes are commonly used in the treatment of solid tumors. However, the toxicity and resistance of these drugs necessitate the search for alternative compounds. Organotin compounds have shown potential in inhibiting cell growth and inducing cell death and autophagy. In this study, the biological activities of different organotin compounds were evaluated, and it was found that tributyltin compounds were more cytotoxic than cisplatin. Additionally, the mechanism of action was attributed to the inhibition of glucose uptake. Furthermore, the tumorigenicity of the cells influenced their susceptibility to the compounds, with highly tumorigenic cells being less affected.
Article
Chemistry, Multidisciplinary
Salvatore Giofre, Consuelo Celesti, Giuseppe Mistretta, Matteo Tiecco
Summary: Deep eutectic solvents (DESs) are green liquids that can be used as substitutes for polluting organic solvents. They have shown promising results in chemical transformations as both solvents and catalysts/reagents. DESs, with a network of H-bonds between donors and acceptors, are particularly effective with aromatic molecules or moieties. This review discusses the recent uses of DESs in chemical transformations involving aromatic benzo-fused and aromatic heterocycle systems, as well as their applications in the suspension and functionalization of aromatic nanostructures.
CURRENT OPINION IN GREEN AND SUSTAINABLE CHEMISTRY
(2023)
Article
Chemistry, Organic
Estefania Capel, Marta Rodriguez-Rodriguez, Uxue Uria, Manuel Pedron, Tomas Tejero, Jose L. Vicario, Pedro Merino
Summary: This study investigates the desymmetrizative ring expansion of alkenylcyclobutanols promoted by halofunctionalization of the alkene moiety with N-bromosuccinimide. Highly enantioenriched cyclopentanones were obtained, demonstrating the effectiveness of the reaction.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
