المؤلفون: Adolfo Pérez-García, Alma Villalobos-Osnaya, María Luisa Hernández-Medel, L. M. Perez-Navarro, Elba O. Medina-Hernandez, Diana Sofía Cabrera-Orejuela, Ana María Espinosa-García, Helena Solleiro-Villavicencio, Mireya León-Hernández, Arianna Rodríguez-Cal Y Mayor, Manli M. Servín-Murillo, José D. Carrillo‐Ruiz, Raúl Serrano-Loyola, Guadalupe Guerrero‐Avendaño, Gustavo Reyes‐Terán, Juan Sierra‐Madero, Gonzalo Salgado-Montes de, Santiago Ávila‐Ríos, Juan Carlos López-Alvarenga, Srinivas Mummidi, Joselín Hernández-Ruiz

مصطلحات موضوعية: Coronavirus Disease 2019, Infectious Diseases, FOS Health sciences, Medicine, Health Sciences, Antiviral Treatment, Favipiravir, Maraviroc, Chemokine, Cytokine storm, Immune system, Immune dysregulation, Viral load, CCR5 receptor antagonist, Immunology, FOS Clinical medicine, Inflammation, Anakinra, Internal medicine, Chemokine receptor, Coronavirus disease 2019 COVID-19, Virus, Disease, Human immunodeficiency virus HIV, Infectious disease medical specialty

الوصف: Multiple studies have established that hyperinflammatory response induced by SARS CoV-2 is a main cause of complications and death in infected subjects. Such dysfunctional immune response has been described as a dysregulated and exacerbated production of cytokines and chemokines that attracts and activates inflammatory cells, which start and sustain pulmonary and systemic damage, thus causing complications that lead to multi organ failure and death. Therefore, we suggest that blocking key inflammation receptors could help to reduce migration and activation of T cells, monocytes/macrophages and neutrophils, thus mitigating the cytokine dysregulation and averting severe complications and death. Importantly, the optimum treatment for COVID-19 severe patients should combine a modulator of the immune response plus a direct antiviral drug against SARS-CoV-2, in order to address both the hyperinflammatory effects of the immune dysregulation and the viral load. Methods: Maraviroc (MVC), a CCR5 antagonist, ... : ملخص أثبتت دراسات متعددة أن الاستجابة الالتهابية المفرطة الناجمة عن فيروس كورونا 2 المرتبط بمتلازمة الجهاز التنفسي الحادة الوخيمة هي السبب الرئيسي للمضاعفات والوفاة لدى الأشخاص المصابين. وقد وصفت هذه الاستجابة المناعية المختلة بأنها إنتاج غير منظم ومتفاقم من السيتوكينات والكيموكينات التي تجذب وتنشط الخلايا الالتهابية، والتي تبدأ وتحافظ على الأضرار الرئوية والجهازية، مما تسبب في مضاعفات تؤدي إلى فشل العديد من الأعضاء والموت. لذلك، نقترح أن منع مستقبلات الالتهاب الرئيسية يمكن أن يساعد في تقليل هجرة وتنشيط الخلايا التائية والخلايا الأحادية/الضامة والعدلات، وبالتالي التخفيف من خلل تنظيم السيتوكين وتجنب المضاعفات الشديدة والموت. الأهم من ذلك، يجب أن يجمع العلاج الأمثل لمرضى كوفيد-19 الحاد بين معدل الاستجابة المناعية بالإضافة إلى دواء مضاد للفيروسات مباشر ضد سارس- كوف-2، من أجل معالجة كل من الآثار الالتهابية المفرطة للخلل المناعي والحمل الفيروسي. الطرق: سيتم تقييم Maraviroc (MVC)، وهو مضاد CCR5، و Favipiravir (FPV)، وهو مضاد للفيروسات، بشكل فردي ومدمج، بالإضافة إلى العلاج المستخدم حاليًا في المستشفى العام في ...

العلاقة: https://dx.doi.org/10.60692/qx3zp-gz147Test

الإتاحة: https://doi.org/10.60692/y8e7p-hy56110.60692/qx3zp-gz147Test

المؤلفون: Zhufang Li, Peter Ackerman, Nannan Zhou, Margaret Gartland, Max Lataillade, Mark I. Cockett, Rose Ronald, Mark Krystal, Jagadish Beloor

المصدر: AIDS (London, England)

مصطلحات موضوعية: maraviroc, Anti-HIV Agents, Immunology, MOTIVATE, HIV Infections, CCR5 receptor antagonist, HIV Envelope Protein gp120, Pharmacology, chemistry.chemical_compound, Basic Science, Cyclohexanes, Viral entry, Drug Resistance, Viral, Consensus sequence, medicine, Humans, Immunology and Allergy, fostemsavir, Cross-resistance, Maraviroc, chemistry.chemical_classification, BRIGHTE, Ibalizumab, Antibodies, Monoclonal, ibalizumab, temsavir, Amino acid, Infectious Diseases, Fostemsavir, chemistry, CCR5 Receptor Antagonists, cross-resistance, medicine.drug

الوصف: Background: Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5 antagonist maraviroc (MVC) are antiretroviral agents that target steps in HIV-1 viral entry. Although mechanisms of inhibition of the three agents are different, it is important to understand whether there is potential for cross-resistance between these agents, as all involve interactions with gp120. Methods: Envelopes derived from plasma samples from participants in the BRIGHTE study who experienced protocol-derived virologic failure (PDVF) and were co-dosed with FTR and either IBA or MVC were analyzed for susceptibility to the agents. Also, CCR5-tropic MVC-resistant envelopes from the MOTIVATE trials were regenerated and studies were performed to understand whether susceptibility to multiple agents were linked. Results: The cloned envelopes exhibited reduced susceptibility to TMR and resistance to the co-dosed agent. At PDVF, emergent or preexisting amino acid substitutions were present at TMR positions of interest. When amino acid substitutions at these positions were reverted to the consensus sequence, full susceptibility to TMR was restored without effecting resistance to the co-dosed agent. In addition, five envelopes from MOTIVATE were regenerated and exhibited R5-tropic-MVC-resistance. Only one exhibited reduced susceptibility to TMR and it contained an M426L polymorphism. When reverted to 426M, full sensitivity for TMR was restored, but it remained MVC resistant. Conclusion: The data confirm that decreased susceptibility to TMR and resistance to IBA or MVC are not linked and that there is no cross-resistance between either of these two agents and FTR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6da40070bb29ca8112803b1156c99bafTest
https://doi.org/10.1097/qad.0000000000003097Test

المؤلفون: Cinzia Borghese, Naike Casagrande, Donatella Aldinucci

المصدر: Haematologica

مصطلحات موضوعية: Receptors, CCR5, business.industry, DNA damage, HIV Infections, Hematology, CCR5 receptor antagonist, Hodgkin Disease, Maraviroc, chemistry.chemical_compound, chemistry, CCR5 Receptor Antagonists, Classical Hodgkin lymphoma, Cancer research, Humans, Medicine, Letters to the Editor, business, Tumor stroma, Trabectedin, DNA Damage, medicine.drug

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3e00e2babe397935e62690459a21209dTest
https://doi.org/10.3324/haematol.2021.279389Test

المؤلفون: E. A. Nickoloff-Bybel, Olimpia Meucci, L. Festa, P. J. Gaskill

المصدر: Retrovirology, Vol 18, Iss 1, Pp 1-35 (2021)
Retrovirology

مصطلحات موضوعية: Receptors, CXCR4, Co-receptor, Receptors, CCR5, Context (language use), HIV Infections, CCR5 receptor antagonist, Review, Biology, chemistry.chemical_compound, Mice, Receptors, HIV, Virology, Animals, Humans, Neuroinflammation, Maraviroc, NeuroHIV, CXCR4, Clinical Trials as Topic, virus diseases, HIV, HIV envelope protein, RC581-607, Signaling, Infectious Diseases, chemistry, CCR5 Receptor Antagonists, Neuroinflammatory Diseases, HIV-1, Neuropathogenesis, Signal transduction, Immunologic diseases. Allergy, Neuroscience, CCR5, Signal Transduction

الوصف: The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e72066a6afb9bd64c2b48ead2ebcf52Test
https://doaj.org/article/32091bbc047e4aadaf828954f9f1d18cTest

المؤلفون: Yang Liu, Lu Lu, Chao Wang, Xinling Wang, Jing Pu, Jiahui Li, Shibo Jiang, Qing X. Li, Huan Wang

المصدر: Journal of Medicinal Chemistry. 64:11460-11471

مصطلحات موضوعية: Receptors, CCR5, Anti-HIV Agents, viruses, Peptide, CCR5 receptor antagonist, Gp41, Structure-Activity Relationship, Chimera (genetics), chemistry.chemical_compound, Viral envelope, Drug Discovery, Humans, Bifunctional, chemistry.chemical_classification, Dose-Response Relationship, Drug, Molecular Structure, virus diseases, Virus Internalization, Virology, HIV Envelope Protein gp41, Heptad repeat, chemistry, Drug Design, CCR5 Receptor Antagonists, HIV-1, Molecular Medicine, Pharmacophore

الوصف: Previous studies have reported the stepwise nature of human immunodeficiency virus type 1 (HIV-1) entry and the pivotal role of coreceptor CCR5 and the gp41 N-terminal heptad repeat (NHR) region in this event. With this in mind, we herein report a dual-targeted drug compound featuring bifunctional entry inhibitors, consisting of a piperidine-4-carboxamide-based CCR5 antagonist, TAK-220, and a gp41 NHR-targeting fusion-inhibitory peptide, C34. The resultant chimeras were constructed by linking both pharmacophores with a polyethylene glycol spacer. One chimera, CP12TAK, exhibited exceptionally potent antiviral activity, about 40- and 306-fold over that of its parent inhibitors, C34 and TAK-220, respectively. In addition to R5-tropic viruses, CP12TAK also strongly inhibited infection of X4-tropic HIV-1 strains. These data are promising for the further development of CP12TAK as a new anti-HIV-1 drug. Results show that this strategy could be extended to the design of therapies against infection of other enveloped viruses.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d036ce3d5a8e4220a2f31260dce28780Test
https://doi.org/10.1021/acs.jmedchem.1c00781Test

المؤلفون: Olivia Blake, Denys Brand, Nicolas Bellini, Emmanuelle Roch, Fabrizio Mammano, Alain Moreau, Martine Braibant, Julie Migraine, Jean-Christophe Plantier, Mélanie Bouvin-Pley, Marie Leoz

المساهمون: Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes (GRAM 1.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), Université de Montréal (UdeM), Institut de Recherches Cliniques de Montréal (IRCM), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mammano, Fabrizio, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

المصدر: AIDS
AIDS, Lippincott, Williams & Wilkins, 2020, 34 (15), pp.2187-2200. ⟨10.1097/qad.0000000000002690⟩
AIDS. Official journal of the international AIDS Society
AIDS. Official journal of the international AIDS Society, 2020, 34 (15), pp.2187-2200. ⟨10.1097/qad.0000000000002690⟩

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, MESH: Glycoproteins, HIV Infections, Context (language use), Viral quasispecies, CCR5 receptor antagonist, Biology, HIV transmission cluster, MESH: HIV-1, MESH: Homosexuality, Male, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Viral Envelope Proteins, Interferon, Genotype, medicine, Humans, Immunology and Allergy, 030212 general & internal medicine, Homosexuality, Male, Glycoproteins, Maraviroc, Infectivity, MESH: Humans, Transmission (medicine), envelope glycoproteins, MESH: CD4-Positive T-Lymphocytes, MESH: HIV Infections, Virology, MESH: Male, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, chemistry, MESH: Viral Envelope Proteins, HIV-1, CD4 þ binding, genetic bottleneck, medicine.drug

الوصف: International audience; Objective: HIV-1 transmission leads to a genetic bottleneck, with one or a few variants of the donor quasispecies establishing an infection in the new host. We aimed to characterize this bottleneck in more detail, by comparing the properties of HIV envelope glycoproteins from acute and chronic infections within the particular context of a male-to-male transmission cluster. Design: We compared the genotypic and phenotypic properties of envelope glycoproteins from viral variants derived from five study participants from the same transmission cluster. Methods: We used single-genome amplification to generate a collection of full-length env sequences. We then constructed pseudotyped viruses expressing selected Env variants from the quasispecies infecting each study participant and compared their infectivities and sensitivities to various entry inhibitors. Results: The genotypic analyses confirmed the genetic bottleneck expected after HIV transmission, with a limited number of variants identified in four study participants during acute infection. However, the transmitted sequences harbored no evident common signature and belonged to various genetic lineages. The phenotypic analyses revealed no difference in infectivity, susceptibility to the CCR5 antagonist maraviroc, the fusion inhibitor enfurvitide or type-I interferon between viruses from participants with acute and chronic infections. The key property distinguishing transmitted viruses was a higher resistance to soluble CD4 þ , correlated with greater sensitivity to occupation of the CD4 þ receptor by the anti-CD4 þ antibodies LM52 and SK3. Conclusion: These results suggest that envelope glycoproteins from transmitted/ founder viruses bind CD4 þ less efficiently than those of viruses from chronic infections.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d92c89e194baabacf613baf0e15f0daeTest
https://doi.org/10.1097/qad.0000000000002690Test

المؤلفون: Shubhnita Singh, Thiago Bruder-Nascimento, Eric J. Belin de Chantemèle, Ariane Bruder-Nascimento

المصدر: Biochem Pharmacol

مصطلحات موضوعية: Male, Chemokine, Receptors, CCR5, Myocytes, Smooth Muscle, CCR5 receptor antagonist, Pharmacology, Biochemistry, CCL5, Article, Muscle, Smooth, Vascular, Maraviroc, Chemokine receptor, Cell Movement, Animals, Chemokine CCL5, Cells, Cultured, biology, Chemistry, virus diseases, NADPH Oxidase 1, NOX4, Cell migration, Vascular System Injuries, Recombinant Proteins, Rats, Mice, Inbred C57BL, Gene Expression Regulation, NOX1, CCR5 Receptor Antagonists, cardiovascular system, biology.protein

الوصف: Background Chemokine (C- Cmotif) ligand 5 (CCL5) and its receptor C-C motif chemokine receptor 5 (CCR5), have been broadly studied in conjunction with infectious pathogens, however, their involvement in cardiovascular disease is not completely understood. NADPH oxidases (Noxs) are the major source of reactive oxygen species (ROS) in the vasculature. Whether the activation of Noxs is CCL5/CCR5 sensitive and whether such interaction initiates vascular injury is unknown. We investigated whether CCL5/CCR5 leads to vascular damage by activating Noxs. Material and Methods We used rat aortic smooth muscle cells (RASMC) to investigate the molecular mechanisms by which CCL5 leads to vascular damage and carotid ligation (CL) to analyze the effects of blocking CCR5 on vascular injury. Results CCL5 induced Nox1 expression in concentration and time-dependent manners, with no changes in Nox2 or Nox4. Maraviroc pre-treatment (CCR5 antagonist, 40uM) blunted CCL5-induced Nox1 expression. Furthermore, CCL5 incubation led to ROS production and activation of Erk1/2 and NFkB, followed by increased vascular cell migration, proliferation, and inflammatory markers. Notably, Nox1 inhibition (GKT771, 10uM) blocked CCL5-dependent effects. In vivo, CL induced pathological vascular remodeling and inflammatory genes and increased Nox1 and CCR5 expression. Maraviroc treatment (25mg/Kg/day) reduced pathological vascular growth and Nox1 expression. Conclusions Our findings suggest that CCL5 activates Nox1 in the vasculature, leading to vascular injury likely via NFkB and Erk1/2. Herein, we place CCR5 antagonists and/or Nox1 inhibitors might be preeminent antiproliferative compounds to reduce the cardiovascular risk associated with medical procedures (e.g. angioplasty) and vascular diseases associated with vascular hyperproliferation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::86d8ba4fe177e9d29af9c4cd8f1afcc1Test
https://europepmc.org/articles/PMC8914050Test/

المؤلفون: Georgette D. Kanmogne, JoEllyn M McMillan, Biju Bhargavan, Shawna M. Woollard

المصدر: Molecular Neurodegeneration
Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-23 (2021)

مصطلحات موضوعية: Amyloid beta, LRP1, Receptor for Advanced Glycation End Products, Tau phosphorylation, CCR5 receptor antagonist, Pharmacology, Neuronal damage, Blood–brain barrier, Maraviroc, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, Alzheimer Disease, Mice, Inbred NOD, NSG mice, medicine, Animals, RC346-429, Molecular Biology, Amyloid beta-Peptides, biology, Human brain microvascular endothelial cells, business.industry, RC952-954.6, Endothelial Cells, Human brain, RAGE, medicine.anatomical_structure, chemistry, Geriatrics, Blood-Brain Barrier, Blood-brain barrier injury, Humanized mouse, biology.protein, HIV-1, Neurology (clinical), Neurology. Diseases of the nervous system, NeuN, Amyloid-beta, business, Monocytes-derived macrophages, CCR5, Research Article

الوصف: Background Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies. Methods NOD/scid–IL-2Rγcnull mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA. Results HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist. Conclusions Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd86f9d13c0c921e76ab89ef58320066Test
http://europepmc.org/articles/PMC8607567Test

المؤلفون: Zhao Yutao, Tian Dongdong, Ouyang Jing, Liu Xiaoqian, Si Hongzong, Wang Yan, Xu Shanyu

المصدر: Letters in Drug Design & Discovery. 17:1036-1046

مصطلحات موضوعية: 0301 basic medicine, 03 medical and health sciences, Quantitative structure–activity relationship, 030104 developmental biology, 0302 clinical medicine, Stereochemistry, Chemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, CCR5 receptor antagonist, IC50, 030217 neurology & neurosurgery

الوصف: Background: In this study, modulators of human Chemotactic cytokine receptor 5 (CCR5) were described using a quantitative structure-activity relationship model (QSAR). This model was based on the molecule’s chemical structure. Methods:: All 56 compounds of CCR5 receptor antagonists were randomly separated into two sets, 43 were reserved for training and the other 13 for testing. In the course of this study, molecular models were drawn using ChemDraw software. By means of Hyperchem software as well as optimized with both AM1 (semi-empirical self-consistent-field molecular orbital) and MM+ (molecular mechanics plus force field), molecular models were described through numerous descriptors using CODESSA software. Results: Linear models were obtained by Heuristic Method (HM) software and nonlinear models were obtained using APS software with optimal descriptor combinations used to build linear QSAR models, involving a group of selected descriptors. As a result, values of the above two different sets were shown to result from 0.82 in testing and 0.86 in training in HM while 0.83 in testing and 0.88 in training in Gene Expression Programming (GEP). Conclusion: From this method, the activity of molecules could be predicted, and the molecular structure could be changed to alter its IC50, avoiding the testing of large numbers of compounds.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::a9cd85df49ecd6f3ab9c7cdb50bdf7aaTest
https://doi.org/10.2174/1570180817666200320105725Test

المؤلفون: J.J. Bleesing, Adam Lane, Michael B. Jordan, Pooja Khandelwal, Mary Christa Krupski, Tsuyoshi Fukuda, Adam S. Nelson, Parinda A. Mehta, Ashley Teusink-Cross, Angela D. M. Kashuba, Kasiani C. Myers, Javier El-Bietar, Sharat Chandra, Michael Grimley, Rebecca A. Marsh, Stella M. Davies

المصدر: Bone Marrow Transplantation. 55:1552-1559

مصطلحات موضوعية: Transplantation, medicine.medical_specialty, business.industry, Phases of clinical research, Hematology, CCR5 receptor antagonist, Gastroenterology, Calcineurin, 03 medical and health sciences, chemistry.chemical_compound, surgical procedures, operative, 0302 clinical medicine, chemistry, immune system diseases, 030220 oncology & carcinogenesis, Internal medicine, Pharmacodynamics, medicine, Methotrexate, Young adult, Adverse effect, business, 030215 immunology, medicine.drug, Maraviroc

الوصف: We report results of a phase II study of maraviroc to prevent acute graft versus host disease (GVHD) in children undergoing allogeneic hematopoietic stem cell transplant (HSCT). Oral maraviroc was added to standard GVHD prophylaxis of a calcineurin inhibitor with either mycophenolate mofetil, methotrexate or steroids from day −3 until day +30 after HSCT. Maraviroc trough levels were analyzed on day 0, +7, 14, and 21. We assessed functional CCR5 blockade by our previously described pharmacodynamic assay. In total, 17 patients were enrolled prospectively. No patient had liver GVHD by day +100. Four patients developed gastrointestinal (GI) GVHD (Grade II upper GI GVHD n = 2, grade III lower GI GVHD n = 2). No adverse effects of maraviroc were observed. Seven patients discontinued maraviroc at a median of day +14 (range day +1–day +29) due to study rules regarding hepatotoxicity (n = 5), renal function decline (n = 1) and withdrawal from study (n = 1). Maraviroc administration led to CCR5 inhibition but was limited by study rules defining hepatotoxicity, leading to frequent drug discontinuation. We cannot comment on the efficacy of maraviroc with our data but speculate that it could have a role in prevention of acute GI GVHD, with adequate compliance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7a73e8ade464104d951daf5f3e234013Test
https://doi.org/10.1038/s41409-020-0888-3Test