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Autophagy Apr 2024In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state resulting in increased secretion of pro-inflammatory factors. We reported...
In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state resulting in increased secretion of pro-inflammatory factors. We reported that C - C chemokine ligand 3 (CCL3), C - C chemokine ligand 4 (CCL4) and C - C chemokine ligand 5 (CCL5) contained in the secretome of activated microglia inhibit neuronal autophagy via a non-cell autonomous mechanism. These chemokines bind and activate neuronal C - C chemokine receptor type 5 (CCR5), which, in turn, promotes phosphoinositide 3-kinase (PI3K) - protein kinase B (PKB, or AKT) - mammalian target of rapamycin complex 1 (mTORC1) pathway activation, which inhibits autophagy, thus causing the accumulation of aggregate-prone proteins in the cytoplasm of neurons. The levels of CCR5 and its chemokine ligands are increased in the brains of pre-manifesting Huntington disease (HD) and tauopathy mouse models. CCR5 accumulation might be due to a self-amplifying mechanism, since CCR5 is a substrate of autophagy and CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation. Furthermore, pharmacological, or genetic inhibition of CCR5 rescues mTORC1-autophagy dysfunction and improves neurodegeneration in HD and tauopathy mouse models, suggesting that CCR5 hyperactivation is a pathogenic signal driving the progression of these diseases.
Topics: Animals; Humans; Mice; Autophagy; Cytokines; Mechanistic Target of Rapamycin Complex 1; Microglia; Molecular Targeted Therapy; Neurons; Receptors, CCR5; Signal Transduction
PubMed: 37358357
DOI: 10.1080/15548627.2023.2221921 -
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 -
Protein & Cell Jun 2010
Review
Topics: Aminoquinolines; Anti-HIV Agents; Benzimidazoles; Benzylamines; Butylamines; CCR5 Receptor Antagonists; CD4 Antigens; Cyclams; Cyclohexanes; HIV-1; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Humans; Maraviroc; Piperazines; Pyrimidines; Receptors, CCR5; Receptors, CXCR4; T-Lymphocytes; Triazoles; Viral Tropism
PubMed: 21204004
DOI: 10.1007/s13238-010-0066-2 -
British Journal of Clinical Pharmacology Nov 2009
Topics: Anti-HIV Agents; Cyclohexanes; Humans; Maraviroc; Pyrrolidinones; Raltegravir Potassium; Triazoles
PubMed: 19916987
DOI: 10.1111/j.1365-2125.2009.03503.x -
Molecular Cancer Research : MCR Jul 2023Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of...
UNLABELLED
Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of action remain elusive. Our objective was to identify secreted factor(s) that mediate the communication between CAFs and ESCC tumor cells with the aim of identifying potential druggable targets. Through unbiased cytokine arrays, we have identified CC motif chemokine ligand 5 (CCL5) as a secreted factor that is increased upon co-culture of ESCC cells and CAFs, which we replicated in esophageal adenocarcinoma (EAC) with CAFs. Loss of tumor-cell-derived CCL5 reduces ESCC cell proliferation in vitro and in vivo and we propose this is mediated, in part, by a reduction in ERK1/2 signaling. Loss of tumor-derived CCL5 reduces the percentage of CAFs recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists, namely Maraviroc. Maraviroc treatment reduced tumor volume, CAF recruitment, and ERK1/2 signaling in vivo, thus, mimicking the effects observed with genetic loss of CCL5. High CCL5 or CCR5 expression is associated with worse prognosis in low-grade esophageal carcinomas.
IMPLICATIONS
These data highlight the role of CCL5 in tumorigenesis and the therapeutic potential of targeting the CCL5-CCR5 axis in ESCC.
Topics: Humans; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Proliferation; Chemokine CCL5; Chemokines; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fibroblasts; Ligands; Maraviroc; Animals
PubMed: 37027010
DOI: 10.1158/1541-7786.MCR-22-0872 -
Drug Design, Development and Therapy 2015The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine... (Review)
Review
The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug-drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Interactions; Drug Resistance, Viral; Genotype; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Mutation; Phenotype; Polypharmacy; Treatment Outcome; Triazoles
PubMed: 26491256
DOI: 10.2147/DDDT.S90580 -
Cancer Research Oct 2019Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient... (Review)
Review
Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and "stemness". Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.
Topics: Animals; Carcinogenesis; Humans; Immunotherapy; Neoplasms; Receptors, CCR5
PubMed: 31292161
DOI: 10.1158/0008-5472.CAN-19-1167 -
The FEBS Journal Jun 2020The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby...
The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby inhibiting virus cellular entry. As noted with other G-protein-coupled receptor family members, the role of the lipid environment in CCR5 signaling remains obscure and very modestly investigated. Controversial literature on the impact of cholesterol (Chol) depletion in HIV infection and CCR5 signaling, including the hypothesis that Chol depletion could inhibit HIV infection, lead us to focus on the understanding of Chol impact in the first stages of receptor activation. To address this aim, the approach chosen was to employ reconstituted model lipid systems of controlled lipid composition containing CCR5 from two distinct expression systems: Pichia pastoris and cell-free expression. The characterization of receptor/ligand interaction in terms of total binding or competition binding assays was independently performed by plasmon waveguide resonance and fluorescence anisotropy, respectively. Maraviroc, a potent receptor antagonist, was the ligand investigated. Additionally, coarse-grained molecular dynamics simulation was employed to investigate Chol impact in the receptor-conformational flexibility and dynamics. Results obtained with receptor produced by different expression systems and using different biophysical approaches clearly demonstrate a considerable impact of Chol in the binding affinity of maraviroc to the receptor and receptor-conformational dynamics. Chol considerably decreases maraviroc binding affinity to the CCR5 receptor. The mechanisms by which this effect occurs seem to involve the adoption of distinct receptor-conformational states with restrained structural dynamics and helical motions in the presence of Chol.
Topics: Cholesterol; HIV; HIV Envelope Protein gp120; HIV Infections; Humans; Ligands; Maraviroc; Receptors, CCR5; Receptors, Virus; Saccharomycetales; Surface Plasmon Resonance; Virus Internalization
PubMed: 31738467
DOI: 10.1111/febs.15145 -
Current Opinion in Virology Feb 2013This review provides an overview of HIV-1 entry inhibitors, with a focus on drugs in the later stages of clinical development. (Review)
Review
PURPOSE OF REVIEW
This review provides an overview of HIV-1 entry inhibitors, with a focus on drugs in the later stages of clinical development.
RECENT FINDINGS
Entry of HIV-1 into target cells involves viral attachment, co-receptor binding, and fusion. Antiretroviral drugs that interact with each step in the entry process have been developed, but only two are currently approved for clinical use. The small molecule attachment inhibitor BMS-663068 has shown potent antiviral activity in early phase studies, and phase 2b trials are currently underway. The postattachment inhibitor ibalizumab has shown antiviral activity in phase 1 and 2 trials; further studies, including subcutaneous delivery of drug to healthy individuals, are anticipated. The CCR5 antagonist maraviroc is approved for use in treatment-naïve and treatment-experienced patients. Cenicriviroc, a small-molecule CCR5 antagonist that also has activity as a CCR2 antagonist, has entered phase 2b studies. No CXCR4 antagonists are currently in clinical trials, but once daily, next-generation injectable peptide fusion inhibitors have entered human trials. Both maraviroc and ibalizumab are being studied for prevention of HIV-1 transmission and/or for use in nucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens.
SUMMARY
Inhibition of HIV-1 entry continues to be a promising target for antiretroviral drug development.
Topics: Antibodies, Monoclonal; Chemoprevention; Clinical Trials as Topic; Cyclohexanes; Disease Transmission, Infectious; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Organophosphates; Piperazines; Triazoles; Virus Internalization
PubMed: 23290628
DOI: 10.1016/j.coviro.2012.12.002 -
HIV-1 subtype C predicted co-receptor tropism in Africa: an individual sequence level meta-analysis.AIDS Research and Therapy Feb 2020Entry inhibitors, such as Maraviroc, hold promise as components of HIV treatment and/or pre-exposure prophylaxis in Africa. Maraviroc inhibits the interaction between... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Entry inhibitors, such as Maraviroc, hold promise as components of HIV treatment and/or pre-exposure prophylaxis in Africa. Maraviroc inhibits the interaction between HIV Envelope gp120 V3-loop and CCR5 coreceptor. HIV-1 subtype C (HIV-1-C) is predominant in Southern Africa and preferably uses CCR5 co-receptor. Therefore, a significant proportion of HIV-1-C CXCR4 utilizing viruses (X4) may compromise the effectiveness of Maraviroc. This analysis examined coreceptor preferences in early and chronic HIV-1-C infections across Africa.
METHODS
African HIV-1-C Envelope gp120 V3-loop sequences sampled from 1988 to 2014 were retrieved from Los Alamos HIV Sequence Database. Sequences from early infections (< 186 days post infection) and chronic infections (> 186 days post infection) were analysed for predicted co-receptor preferences using Geno2Pheno [Coreceptor] 10% FPR, Phenoseq-C, and PSSMsinsi web tools. V3-loop diversity was determined, and viral subtype was confirmed by phylogenetic analysis. National treatment guidelines across Africa were reviewed for Maraviroc recommendation.
RESULTS
Sequences from early (n = 6316) and chronic (n = 7338) HIV-1-C infected individuals from 10 and 15 African countries respectively were available for analyses. Overall, 518/6316 (8.2%; 95% CI 0.7-9.3) of early sequences were X4, with Ethiopia and Malawi having more than 10% each. For chronic infections, 8.3% (95% CI 2.4-16.2) sequences were X4 viruses, with Ethiopia, Tanzania, and Zimbabwe having more than 10% each. For sequences from early chronic infections (< 1 year post infection), the prevalence of X4 viruses was 8.5% (95% CI 2.6-11.2). In late chronic infections (≥ 5 years post infection), X4 viruses were observed in 36% (95% CI - 16.3 to 49.9), with two countries having relatively high X4 viruses: South Africa (43%) and Malawi (24%). The V3-loop amino acid sequence were more variable in X4 viruses in chronic infections compared to acute infections, with South Africa, Ethiopia and Zimbabwe showing the highest levels of V3-loop diversity. All sequences were phylogenetically confirmed as HIV-1-C and clustered according to their co-receptor tropism. In Africa, Maraviroc is registered only in South Africa and Uganda.
CONCLUSIONS
Our analyses illustrate that X4 viruses are present in significantly similar proportions in early and early chronic HIV-1 subtype C infected individuals across Africa. In contrast, in late chronic infections, X4 viruses increase 3-5 folds. We can draw two inferences from our observations: (1) to enhance the utility of Maraviroc in chronic HIV subtype C infections in Africa, prior virus co-receptor determination is needed; (2) on the flip side, research on the efficacy of CXCR4 antagonists for HIV-1-C infections is encouraged. Currently, the use of Maraviroc is very limited in Africa.
Topics: Drug Resistance, Multiple, Viral; Genotype; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Maraviroc; Phylogeny; Receptors, CXCR4; Receptors, HIV; Sequence Analysis, DNA; South Africa; Viral Tropism
PubMed: 32033571
DOI: 10.1186/s12981-020-0263-x