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AIDS Research and Human Retroviruses Apr 2022The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral... (Randomized Controlled Trial)
Randomized Controlled Trial
The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK ( < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model ( < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.
Topics: Anti-HIV Agents; Anti-Infective Agents; Anti-Retroviral Agents; Cyclohexanes; Female; HIV Infections; Humans; Male; Maraviroc
PubMed: 34384282
DOI: 10.1089/AID.2021.0096 -
Frontiers in Immunology 2022
Topics: HIV-1; Receptors, CCR5
PubMed: 36330512
DOI: 10.3389/fimmu.2022.1054430 -
Expert Opinion on Therapeutic Targets May 2024
Topics: Humans; Receptors, CCR5; Animals; Non-alcoholic Fatty Liver Disease; Molecular Targeted Therapy; CCR5 Receptor Antagonists
PubMed: 38857170
DOI: 10.1080/14728222.2024.2366880 -
BioRxiv : the Preprint Server For... Nov 2022In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and...
In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A investigation into 18 small molecules and 3 biologics was conducted in cell culture and the impact of treatment on viral titer was quantified by plaque assay. The investigation identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection. Confocal microscopy with over expressed S-protein demonstrated that Maraviroc reduced the extent of S-protein mediated cell fusion as observed by fewer multinucleate cells in the context of drug-treatment. Mathematical modeling of drug-dependent viral multiplication dynamics revealed that prolonged drug treatment will exert an exponential decrease in viral load in a multicellular/tissue environment. Taken together, the data demonstrate that Maraviroc, Fingolimod, Atorvastatin and Nitazoxanide inhibit SARS-CoV-2 in cell culture.
PubMed: 32817953
DOI: 10.1101/2020.08.12.246389 -
Cells Apr 2024Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including... (Review)
Review
Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome. Despite viral suppression with combination antiretroviral therapy (ART), people living with HIV (PLWH) are prone to many comorbidities, including neurological and neuropsychiatric complications, cardiovascular and metabolic diseases, premature aging, and malignancies. HIV and viral proteins can directly contribute to the development of these comorbidities. However, with the continued high prevalence of these comorbidities despite viral suppression, it is likely that ART or some antiretroviral (ARVs) drugs contribute to the development and persistence of comorbid diseases in PLWH. These comorbid diseases often involve vascular activation, injury, and dysfunction. The purpose of this manuscript is to review the current literature on ARVs and the vascular endothelium in PLWH, animal models, and in vitro studies. I also summarize evidence of an association or lack thereof between ARV drugs or drug classes and the protection or injury/dysfunction of the vascular endothelium and vascular diseases.
Topics: Animals; Humans; Anti-HIV Agents; Anti-Retroviral Agents; Endothelium, Vascular; HIV Infections
PubMed: 38667287
DOI: 10.3390/cells13080672 -
Journal of Cancer Research and Clinical... Dec 2023The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma...
PURPOSE
The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist.
METHODS
A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed.
RESULTS
The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis.
CONCLUSIONS
The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.
Topics: Humans; Animals; Mice; Maraviroc; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Retrospective Studies; Cell Line, Tumor; Mouth Neoplasms; RNA, Small Interfering; Head and Neck Neoplasms; Tumor Microenvironment; Chemokine CCL5
PubMed: 37831273
DOI: 10.1007/s00432-023-05443-1 -
European Journal of Medicinal Chemistry Dec 2020C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and... (Review)
Review
C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and mobilization. In the 1980s, several reports suggest that lack of the HIV-1 co-receptor, the chemokine receptor CCR5, offers protection against HIV infection. Later, it was shown that CCR5 was confirmed to be the most common co-receptor for the HIV-1 virus R5 strain. In recent years, many studies have shown that CCR5 is closely related to the development of various cancers and inflammations to facilitate the discovery of CCR5 antagonists. There are many types of CCR5 antagonists, mainly including chemokine derivatives, non-peptide small molecule compounds, monoclonal antibodies, and peptide compounds. This review focus on the recent research processes and pharmacological effects of CCR5 antagonists such as Maraviroc, TAK-779 and PRO 140. After focusing on the therapeutic effect of CCR5 antagonists on AIDS, it also discusses the therapeutic prospect of CCR5 in other diseases such as inflammation and tumor.
Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Anti-Inflammatory Agents; Antineoplastic Agents; CCR5 Receptor Antagonists; HIV-1; HIV-2; Humans; Inflammation; Neoplasms; Receptors, CCR5
PubMed: 32947226
DOI: 10.1016/j.ejmech.2020.112819 -
Drug Metabolism and Disposition: the... Sep 2019Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several...
Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several autoimmune, cancer, and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ATP-binding cassette (ABC) efflux transporters that have a recognized role in the protection of a developing fetus: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance protein 2 (ABCC2). We found that maraviroc does not inhibit any of the three studied ABC transporters and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine P-glycoprotein (Abcb1) expressed in Madin-Darby canine kidney II (MDCKII) cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the fetal-to-maternal direction, which suggests that ABCB1/Abcb1 facilitates in situ maraviroc transport. This transplacental transport was saturable and significantly diminished after the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood. SIGNIFICANCE STATEMENT: Antiretroviral drug maraviroc shows low toxicity and is thus a good candidate for prevention of mother-to-child transmission of human immunodeficiency virus when failure of recommended therapy occurs. Using in vitro cell-based experiments and in situ dually perfused rat term placenta, we examined maraviroc interaction with the placental ABC drug transporters ABCB1, ABCG2, and ABCC2. We demonstrate for the first time that placental ABCB1 significantly reduces mother-to-fetus transport of maraviroc, which suggests that ABCB1 may be responsible for the low cord-blood/maternal-blood ratio observed in humans.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; CCR5 Receptor Antagonists; Dogs; Female; Fetus; HIV Infections; Humans; Madin Darby Canine Kidney Cells; Maraviroc; Maternal-Fetal Exchange; Models, Animal; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Permeability; Placenta; Placental Circulation; Pregnancy; Pregnancy Complications, Infectious; Rats
PubMed: 31266750
DOI: 10.1124/dmd.119.087684 -
Radiology and Oncology Nov 2019Background Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to... (Review)
Review
Background Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to therapy resistant glioblastoma stem cells in addition to intertumour heterogeneity that is due to infiltration of a plethora of host cells. Besides endothelial cells, mesenchymal stem cells and their differentiated progenies, immune cells of various differentiation states, including monocytes, comprise resident, brain tumour microenvironment. There are compelling evidence for CCL5/CCR5 in the invasive and metastatic behaviour of many cancer types. CCR5, a G-protein coupled receptor, known to function as an essential co-receptor for HIV entry, is now known to participate in driving tumour heterogeneity, the formation of cancer stem cells and the promotion of cancer invasion and metastasis. Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple negative breast cancer (TNBC) or a small molecule inhibitor (maraviroc) for metastatic colon cancer. There are important CCL5 and CCR5 structure and signalling mechanisms in glioblastoma. In addition, the CCL5/CCR5 axis directs infiltration and interactions with monocytes/macrophages and mesenchymal stem cells, comprising glioblastoma stem cell niches. Conclusions CCR5 is highly expressed in glioblastoma and is associated with poor prognosis of patients. CCL5/CCR5 is suggested to be an excellent new target for glioblastoma therapy. The molecular mechanisms, by which chemoattractant and receptor respond within the complex tissue microenvironment to promote cancer stem cells and tumour heterogeneity, should be considered in forthcoming studies.
Topics: Brain Neoplasms; CCR5 Receptor Antagonists; Chemokine CCL5; Disease Progression; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Receptors, CCR5; Tumor Microenvironment
PubMed: 31747383
DOI: 10.2478/raon-2019-0057 -
Journal of Biomolecular Structure &... Aug 2021Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2....
Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been performed by a virtual drug repurposing approach. First, drug shape-based screening (among FDA approved drugs) with a known template of MTase inhibitor, sinefungin was done and best compounds with high similarity scores were selected. In addition to the selected compounds, 4 nucleoside analogs of anti-viral (Raltgravir, Maraviroc and Favipiravir) and anti-inflammatory (Prednisolone) drugs were selected for further investigations. Then, binding energies and interaction modes were found by molecular docking approaches and compouds with lower energy were selected for further investigation. After that, Molecular dynamics (MD) simulation was carried to test the potential selected compounds in a realistic environment. The results showed that Raltegravir and Maraviroc among other compounds can bind strongly to the active site of the protein compared to sinefungin, and can be potential candidates to inhibit NSP-16. Also, the MD simulation results suggested that the Maraviroc and Raltegravir are more effective drug candidates than Sinefungin for inhibiting the enzyme. It is concluded that Raltegravir and Maraviroc which may be used in the treatment of COVID-19 after Invitro and invivo studies and clinical trial for final confirmation of drug effectiveness. Communicated by Ramaswamy H. Sarma.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Molecular Docking Simulation; SARS-CoV-2
PubMed: 32573355
DOI: 10.1080/07391102.2020.1779133