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
Chemistry, Medicinal
Dongwei Kang, Yanying Sun, Da Feng, Shenghua Gao, Zhao Wang, Lanlan Jing, Tao Zhang, Xiangyi Jiang, Hao Lin, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Summary: This article reports the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b and 16c exhibited superior potency against a panel of HIV-1-resistant strains, especially for specific mutations. They also showed moderate RT enzyme inhibition and favorable pharmacokinetic and safety properties, making them promising candidates for further development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Dongwei Kang, Yanying Sun, Da Feng, Shenghua Gao, Zhao Wang, Lanlan Jing, Tao Zhang, Xiangyi Jiang, Hao Lin, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Summary: In this study, dihydrofuro[3,4-d]pyrimidine derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Compounds 14b and 16c exhibited superior antiviral activity and RT enzyme inhibition, making them promising leads for further development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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)
Article
Chemistry, Organic
Matteo A. . Tallarida, Fabrizio Olivito, Claudio D. Navo, Vincenzo Algieri, Antonio Jiritano, Paola Costanzo, Ana Poveda, Maria J. Moure, Jesus Jimenez-Barbero, Loredana Maiuolo, Gonzalo Jimenez-Oses, Antonio De Nino
Summary: The synthesis of polysubstituted spirocyclopropyl oxindoles using rare-earth metal (REM) salts, particularly Sc(OTf)3, was achieved with high diastereoselectivity (<= 94:6:0:0) in a multicomponent reaction. Density functional theory calculations on the model reaction confirmed the observed selectivity and demonstrated that the coordinating capabilities and oxophilicity of the metal played a crucial role in inducing the formation of one main diastereoisomer.
Review
Cell Biology
Athanasios-Dimitrios Bakasis, Theodoros Androutsakos
Summary: Since the introduction of ART in 1996, the lifespan of PLWH has increased and the major causes of mortality have shifted towards cardiovascular and liver diseases. HIV itself and various liver diseases may contribute to liver damage and subsequent LF in PLWH. Among ART drug classes, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, appear to pose the greatest risk for LF.
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
Medicine, General & Internal
Yuting Tan, Songjie Wu, Yajun Yan, Shi Zou, Ling Feng, Wei Guo, Mengmeng Wu, Mingqi Luo, Ke Liang
Summary: LPV/r-NRTIs have been widely used among pregnant women living with HIV in Hubei Province, China. The use of LPV/r-NRTIs is associated with an increased risk of low birthweight and this risk should be continuously monitored whether LPV/r-NRTIs is initiated before or during pregnancy.
FRONTIERS IN MEDICINE
(2023)
Article
Infectious Diseases
Minh Patrick Le, Lucile Pencole, Gilles Peytavin, Florian Bouchet-Crivat, Laurent Mandelbrot
Summary: In this study, it was found that doravirine crosses the placenta and accumulates within it, potentially providing a prophylaxis for vertical HIV transmission. Further investigation is needed to determine the safety and efficacy of this new antiretroviral agent in pregnancy.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Jirayu Kammarabutr, Panupong Mahalapbutr, Hisashi Okumura, Peter Wolschann, Thanyada Rungrotmongkol
Summary: This study indicates that certain anti-HIV drugs may have higher susceptibility against HBV-RT enzyme, potentially serving as a promising drug option for HBV-infected patients with 3TC resistance.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Immunology
Nisha Holay, Alexander Somma, Mark Duchow, Milad Soleimani, Anna Capasso, Srividya Kottapalli, Joshua Rios, Uma Giri, Jennifer Diamond, Anna Schreiber, Anthony D. Piscopio, Carla van den Berg, S. Gail Eckhardt, Todd A. Triplett
Summary: Histone deacetylase inhibitors (HDACi) have potential for the treatment of malignancies, but their direct effects on T cells need further investigation. This study found that a novel class-selective HDACi rapidly increased CD4 and CD8 T cell frequencies in the blood, but the effects were transient. Therefore, treatment regimens combining HDACi with immunotherapy should take into account acute T cell effects.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Andreu Gazquez Casals, Alex J. Berkowitz, Alice J. Yu, Hope E. Waters, Daniel V. Schiavone, Diana M. Kapkayeva, Lynda A. Morrison, Ryan P. Murelli
Summary: Alpha-Hydroxytropolones (alpha HTs) have shown potent antiviral activity against herpes simplex virus-1 and -2 (HSV-1 and HSV-2) in cell culture, and have the potential to be developed as antiviral drugs targeting these viruses. The evaluation of a library of amide-substituted alpha HTs against HSV-1 and a subset against HSV-2 showed that lipophilicity and rigidity are important for their anti-HSV potency. A targeted library of 4 amide-appended alpha HTs was synthesized and tested, with the most potent compound having an EC50 of 72 nM for viral inhibition. The ease of synthesis of these compounds makes them valuable for future anti-HSV drug development.
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
Angelica Ferro, Dafni Graikioti, Emre Gezer, Constantinos M. M. Athanassopoulos, Muriel Cuendet
Summary: Although proteasome inhibitors have been used as the main treatment for multiple myeloma, patients often relapse and become resistant to drugs. Combining proteasome and histone deacetylase inhibitors has been found to be more effective, as it enhances anti-myeloma activity and improves patient outcomes. Hybrid molecules that combine the pharmacophores of entinostat and bortezomib have been synthesized and shown to have strong antiproliferative activity in multiple myeloma cells, including those resistant to bortezomib, as well as inhibiting histone deacetylase and proteasome activity.
Review
Pharmacology & Pharmacy
Mohammad Ullah Nayan, Brady Sillman, Mahmudul Hasan, Suyash Deodhar, Srijanee Das, Ashrafi Sultana, Nam Thai Hoang Le, Vicente Soriano, Benson Edagwa, Howard E. Gendelman
Summary: Adherence to daily ART is a barrier in HIV treatment and prevention. Long-acting ARVs and other formulations are now in use or in development to simplify treatment regimens. However, challenges remain in dosing intervals, administration, and access. Future developments in ultra-long-acting ARTs may offer improved treatment options.
ADVANCED DRUG DELIVERY REVIEWS
(2023)
Editorial Material
Hematology
Charles R. M. Bangham
Summary: In this study, Kogure et al identify new oncogenic drivers, noncoding and structural mutations, and a novel molecular signature that distinguishes the leukemic from the lymphomatous forms of adult T-cell leukemia/lymphoma (ATL) through a whole-genome analysis of 150 cases.
Article
Biochemistry & Molecular Biology
Sonia Andre, Morgane Picard, Renaud Cezar, Florence Roux-Dalvai, Aurelie Alleaume-Butaux, Calaiselvy Soundaramourty, Andre Santa Cruz, Ana Mendes-Frias, Clarisse Gotti, Mickael Leclercq, Alexandre Nicolas, Alexandra Tauzin, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, Antonio Gil Castro, Lucy Kundura, Paul Loubet, Albert Sotto, Laurent Muller, Jean-Yves Lefrant, Claire Roger, Pierre-Geraud Claret, Sandra Duvnjak, Tu-Anh Tran, Gina Racine, Ouafa Zghidi-Abouzid, Pierre Nioche, Ricardo Silvestre, Arnaud Droit, Fabrizio Mammano, Pierre Corbeau, Jerome Estaquier
Summary: By comparing COVID-19 patients with healthy donors, the study found a strong correlation between T cell apoptosis and lymphopenia in severe cases. The plasma levels of soluble FasL (sFasL) and T cell surface expression of Fas/CD95 were positively correlated with T cell death and CD4 T cell counts. The study also identified modulations in the Bcl-2 family and demonstrated the potential of a pan-caspase inhibitor, Q-VD, to prevent T cell apoptosis and enhance Th1 transcripts.
CELL DEATH AND DIFFERENTIATION
(2022)
Correction
Immunology
Hiroo Katsuya, Lucy B. M. Cook, Aileen G. Rowan, Anat Melamed, Jocelyn Turpin, Jumpei Ito, Saiful Islam, Paola Miyazato, Benjy Jek Yang Tan, Misaki Matsuo, Toshikazu Miyakawa, Hirotomo Nakata, Shuzo Matsushita, Graham P. Taylor, Charles R. M. Bangham, Shinya Kimura, Yorifumi Satou
JOURNAL OF INFECTIOUS DISEASES
(2022)
Review
Cardiac & Cardiovascular Systems
Sarah Halawa, Soni S. Pullamsetti, Charles R. M. Bangham, Kurt R. Stenmark, Peter Dorfmuller, Maria G. Frid, Ghazwan Butrous, Nick W. Morrell, Vinicio A. de Jesus Perez, David I. Stuart, Kevin O'Gallagher, Ajay M. Shah, Yasmine Aguib, Magdi H. Yacoub
Summary: This article discusses the potential causes of COVID-19 heterogeneity and summarizes the pathobiology of the disease, with a focus on the role of the pulmonary vasculature in the acute stage and the potential for developing chronic pulmonary hypertension.
NATURE REVIEWS CARDIOLOGY
(2022)
Article
Multidisciplinary Sciences
Alexander J. Mentzer, Nicole Brenner, Naomi Allen, Thomas J. Littlejohns, Amanda Y. Chong, Adrian Cortes, Rachael Almond, Michael Hill, Simon Sheard, Gil McVean, Rory Collins, Adrian V. S. Hill, Tim Waterboer
Summary: The authors designed a multiplex serology platform to measure quantitative antibody responses against 20 infectious agents and confirmed their associations with sociodemographic characteristics, HLA genetic variants, and disease outcomes. The findings provide valuable insights into host-pathogen-disease relationships.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Anat Melamed, Tomas W. Fitzgerald, Yuchuan Wang, Jian Ma, Ewan Birney, Charles R. M. Bangham
Summary: Human retroviruses HTLV-1 and HIV-1 persist in the body as a reservoir of latently infected T cell clones. The study found that the position of the provirus in the nucleus, its distance from the centromere, and the intensity of local host genome transcription are important factors determining clonal survival. Similar factors were also found to explain clonal persistence of HIV-1. This research highlights the importance of the intranuclear and intrachromosomal location of the provirus and host transcription intensity in the persistence of human retroviruses.
Article
Immunology
Annika P. Schnell, Stephan Kohrt, Aris Aristodemou, Graham P. Taylor, Charles R. M. Bangham, Andrea K. Thoma-Kress
Summary: The pan-HDACi Panobinostat and class I HDACi Romidepsin have been identified as potent agents in enhancing Tax expression in HTLV-1. However, the increase in Tax protein levels is only moderate.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Christy Prawiro, Tom D. Bunney, Charis Kampyli, Hiroko Yaguchi, Matilda Katan, Charles R. M. Bangham
Summary: Adult T-cell leukemia/lymphoma (ATL) development involves HTLV-1 infection and somatic mutations, with phospholipase C gamma1 (PLCG1) being the most frequently mutated gene. The functional consequences of PLCG1 mutations in cancer cells have not been characterized.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Biochemistry & Molecular Biology
Alexis Yero, Ralph-Sydney Mboumba Bouassa, Petronela Ancuta, Jerome Estaquier, Mohammad-Ali Jenabian
Summary: Th17-polarized CD4+ effector T-cells and their immunosuppressive regulatory T-cell (Treg) counterparts play important roles at mucosal interfaces. Alterations in the Th17/Treg ratios contribute to disease progression in HIV and SIV infections. The dysregulation of metabolic pathways during HIV-1 infection affects the Th17/Treg balance.
CYTOKINE & GROWTH FACTOR REVIEWS
(2023)
Article
Virology
Nazanin Mohammadzadeh, Na Zhang, William G. Branton, Ouafa Zghidi-Abouzid, Eric A. Cohen, Benjamin B. Gelman, Jerome Estaquier, Linglong Kong, Christopher Power
Summary: Despite effective antiretroviral therapy (ART), HIV-encoded DNA, RNA, and proteins can still be found in the brain, leading to neurocognitive impairments. The expression and regulation of antiretroviral host restriction factors (RFs) in the brain for HIV and SIV remain unknown. This study examined the transcriptomic profile of RF genes and found significant increases in RF expression in the brains of HIV-infected individuals with encephalitis. ART interruption resulted in induced expression of RF genes, suggesting the brain's RF profile can be influenced by ART.
Article
Microbiology
Saumya Ramanayake, Dale A. Moulding, Yuetsu Tanaka, Abhyudai Singh, Charles R. M. Bangham
Summary: We studied the kinetics of Tax expression in two naturally-infected, non-malignant T-cell clones using live-cell imaging and mathematical modeling. Single-cell analysis revealed five patterns of Tax expression, with most Tax-positive cells expressing continuously over a 30-hour period. The average duration of Tax expression in the two clones was 94 and 417 hours, respectively, as estimated by mathematical modeling. Tax expression was associated with transiently decreased proliferation, increased apoptosis, enhanced activation of DNA damage response pathways, and delayed progression through the cell cycle. Extended observation showed that as cells ceased Tax expression, there was an increase in the proportion of proliferating cells and a decrease in the percentage of apoptotic cells, resulting in a greater net growth of the initially Tax-positive population. Tax-expressing cells also formed cell clumps and exhibited reduced cell movement. These findings help reconcile previous conflicting observations regarding the impact of Tax on the host cell.
Review
Hematology
Charles R. M. Bangham
Summary: Human T-cell leukemia virus type 1 (HTLV-1) causes ATL in 5% of infected people and HTLV-1-associated myelopathy in 0.3% to 4% of them. Reliable treatments are lacking, but there have been recent advances in ATL prevention and treatment. Understanding the virus's persistence in the host and its role in oncogenesis is crucial.
Article
Multidisciplinary Sciences
Andre Santa Cruz, Ana Mendes-Frias, Marne Azarias-da-Silva, Sonia Andre, Ana Isabel Oliveira, Olga Pires, Marta Mendes, Barbara Oliveira, Marta Braga, Joana Rita Lopes, Rui Domingues, Ricardo Costa, Luis Neves Silva, Ana Rita Matos, Cristina Angela, Patricio Costa, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, Antonio Gil Castro, Jerome Estaquier, Ricardo Silvestre
Summary: Based on our study, individuals with post-acute sequelae SARS-CoV-2 (PASC) exhibit persisting immunological dysfunction, including changes in mucosal immune parameters, redistribution of mucosal CD8(+)beta 7Integrin(+) T cells, and IgA, indicating potential viral persistence and mucosal involvement in the etiopathology of PASC at six months following infection.
NATURE COMMUNICATIONS
(2023)
Article
Microbiology
Aris E. N. R. Aristodemou, David Rueda, Graham R. Taylor, Charles R. M. Bangham, Patrick L. R. Green
Summary: This study analyzed the expression changes of host and viral genes during HTLV-1 reactivation in cells isolated from patients' blood. The study found that changes in viral expression may be related to changes in a group of epigenetic modifiers, which may contribute to the virus returning to a latent state after activation. In addition, the study also identified three deubiquitinases that can promote viral expression. These findings are of great importance for further understanding the lifecycle and infection mechanisms of HTLV-1.
Article
Multidisciplinary Sciences
Marne Azarias Da Silva, Pierre Nioche, Calaiselvy Soudaramourty, Anne Bull-Maurer, Mounira Tiouajni, Dechuan Kong, Ouafa Zghidi-Abouzid, Morgane Picard, Ana Mendes-Frias, Andre Santa-Cruz, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, Antonio Gil Castro, Paul Loubet, Albert Sotto, Laurent Muller, Jean-Yves Lefrant, Claire Roger, Pierre-Geraud Claret, Sandra Duvnjak, Tu-Anh Tran, Kenzo Tokunaga, Ricardo Silvestre, Pierre Corbeau, Fabrizio Mammano, Jerome Estaquier
Summary: This study evaluated the quantity, quality, and persistence of antibodies in individuals who received mRNA vaccines and compared them with previously infected individuals who were also vaccinated. The findings showed that three doses of mRNA vaccine were needed to match the immune responses of preinfected individuals. Additionally, repeated vaccination significantly improved the cross-reactivity of antibodies against spike variants. The study also reported lower levels of germinal center activation and formation in vaccinated individuals, potentially explaining the shorter duration and lower quality of induced antibodies.