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1.
Nat Commun ; 14(1): 159, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631487

RESUMO

TGFß1 induces age-related bone loss by promoting degradation of TNF receptor-associated factor 3 (TRAF3), levels of which decrease in murine and human bone during aging. We report that a subset of neutrophils (TGFß1+CCR5+) is the major source of TGFß1 in murine bone. Their numbers are increased in bone marrow (BM) of aged wild-type mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CCL5, suggesting that TRAF3 in MPCs limits TGFß1+CCR5+ neutrophil numbers in BM of young mice. During aging, TGFß1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFß1+CCR5+ neutrophil numbers in BM where they induce bone loss. TGFß1+CCR5+ neutrophils decreased bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, reduced TGFß1+CCR5+ neutrophil numbers in BM and increased bone mass in aged mice. 15-mon-old mice with TGFßRII specifically deleted in MPCs had lower numbers of TGFß1+CCR5+ neutrophils in BM and higher bone volume than wild-type littermates. We propose that pharmacologic reduction of TGFß1+CCR5+ neutrophil numbers in BM could treat or prevent age-related osteoporosis.


Assuntos
Neutrófilos , Osteoporose , Camundongos , Masculino , Humanos , Animais , Idoso , Neutrófilos/metabolismo , Medula Óssea/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Maraviroc , Receptores CCR5/genética , Receptores CCR5/metabolismo
2.
Int J Mol Sci ; 23(24)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36555761

RESUMO

Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC50 value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.


Assuntos
Inibidores da Fusão de HIV , Infecções por HIV , Humanos , Maraviroc/farmacologia , HIV/metabolismo , Simulação de Acoplamento Molecular , Cisteína , Infecções por HIV/tratamento farmacológico , Receptores de Quimiocinas , Simulação de Dinâmica Molecular , Receptores CCR5/metabolismo , Inibidores da Fusão de HIV/farmacologia , Inibidores da Fusão de HIV/química
3.
Viruses ; 14(11)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36366513

RESUMO

With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a gp41-targeted fusion inhibitor. The resulting CCL5 5p12 5m-C37 fusion protein was expressed in E. coli and proved to be capable of inhibiting R5 HIV-1 strains with low to sub-picomolar IC50, maintaining its antagonism toward CCR5. In addition, CCL5 5p12 5m-C37 inhibits R5/X4 and X4 HIV-1 strains in the picomolar concentration range. The combination of CCL5 5p12 5m-C37 with tenofovir (TDF) exhibited a synergic effect, promoting this antiviral cocktail. Interestingly, a CCR5-targeted combination of maraviroc (MVC) with CCL5 5p12 5m-C37 led to a synergic effect that could be explained by an extensive engagement of different CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Receptores CCR5/genética , Receptores CCR5/metabolismo , Escherichia coli/metabolismo , Maraviroc/farmacologia , Maraviroc/uso terapêutico , Infecções por HIV/metabolismo , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico
4.
PLoS One ; 17(10): e0275269, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251708

RESUMO

CC Chemokine receptor 5 (CCR5), a member of the Superfamily of G Protein-Coupled Receptors (GPCRs), is an important effector in multiple physiopathological processes such as inflammatory and infectious entities, including central nervous system neuroinflammatory diseases such as Alzheimer's disease, recovery from nervous injuries, and in the HIV-AIDS infective processes. Thus, CCR5 is an attractive target for pharmacological modulation. Since maraviroc was described as a CCR5 ligand that modifies the HIV-AIDS progression, multiple efforts have been developed to describe the functionality of the receptor. In this work, we characterized key structural features of the CCR5 receptor employing extensive atomistic molecular dynamics (MD) in its apo form and in complex with an endogenous agonist, the chemokine CCL5/RANTES, an HIV entry inhibitor, the partial inverse agonist maraviroc, and the experimental antagonists Compound 21 and 34, aiming to elucidate the structural features and mechanistic processes that constitute its functional states, contributing with structural details and a general understanding of this relevant system.


Assuntos
Inibidores da Fusão de HIV , Infecções por HIV , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , Quimiocina CCL5/farmacologia , Infecções por HIV/tratamento farmacológico , Humanos , Imidazóis , Ligantes , Maraviroc/uso terapêutico , Receptores CCR5 , Sulfonamidas , Tiofenos
5.
Pediatr Infect Dis J ; 41(11): 885-890, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35980827

RESUMO

BACKGROUND: Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options. METHODS: Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens. RESULTS: A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL. CONCLUSIONS: While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.


Assuntos
Infecções por HIV , Nevirapina , Adulto , Alcinos , Benzoxazinas/uso terapêutico , Ciclopropanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Maraviroc/uso terapêutico
6.
Angew Chem Int Ed Engl ; 61(41): e202210312, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35972406

RESUMO

Amides are ubiquitous in physical and life sciences. Given the significant abundance of arenes, dearomative aminocarbonylation of arenes would lead to a large and underexplored chemical space for amide discovery. However, such reactions are challenging due to the high degree of resonance stabilization and selectivity issues. Herein, we disclose an unprecedented dearomative trifluoromethylative aminocarbonylation of arenes via bifunctional coordination to chromium, providing a modular platform for the construction of amides possessing trifluoromethyl (CF3 ) groups and three-dimensional rings. Its versatility further enabled a switchable difluoromethylation or trifluoromethylation aminocarbonylation of arene C-H bonds. A possible mechanism was proposed based on control experiments. Finally, the synthetic utility was well demonstrated by diverse applications in the total synthesis of CF3 -functionalized amide-type drugs, including praziquantel, nateglinide, maraviroc and alloyohimbane.


Assuntos
Cromo , Praziquantel , Amidas/química , Catálise , Maraviroc , Nateglinida
7.
Immun Inflamm Dis ; 10(9): e687, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36039647

RESUMO

BACKGROUND: The C-C chemokine receptor 5 (CCR5) is mainly expressed in a variety of immune cells. It interacts with multiple chemokine ligands that mediate the trafficking and recruitment of effector cells toward sites of inflammation. CCR5 not only plays a critical role in cell growth, activation, differentiation, adhesion, and migration but also participates in the development of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. METHODS: This is a literature review article. The research design method is an evidence-based rapid review. The present discourse aim is first to scrutinize and assess the available literature on CCR5 and acute GVHD. Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed. RESULTS: CCR5 is a marker of GVHD effector cells, and CCR5 expression is elevated when acute GVHD occurs. CCR5 blockade with maraviroc in clinical trials results in a low incidence of acute GVHD. The immune mechanism includes that CCR5 blockade inhibits donor T cell migration and recruitment toward target organs, reduces the absolute numbers of donor T cells, is capable of slightly suppressing dendritic cell maturation, and reduces the percentage of Th1 and Th17 subsets. CCR5 blockade also inhibits internalization and activation of chemokines, inhibits proliferation and chemotaxis of T cells, and decreases the production of TNF-α and IFN-γ. In addition, there may be a form of crosstalk between CCR5 and CCR2. Inconsistently, infusion of CCR5-/- Tregs into lethally irradiated mice significantly increased the infiltration of CD4+ and CD8+ T cells into the liver, resulting in earlier and more severe GVHD. CONCLUSION: This review indicates that CCR5 plays an important role in pathogenesis and development of acute GVHD. Elucidating its role in different immune cells will aid the development of targeted therapeutic treatments.


Assuntos
Doença Enxerto-Hospedeiro , Animais , Linfócitos T CD8-Positivos , Quimiocinas , Quimiocinas CC , Maraviroc/farmacologia , Camundongos , Receptores CCR5/genética
8.
Sci Rep ; 12(1): 12945, 2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902720

RESUMO

One-third of pneumococcal meningitis (PM) survivors suffer from neurological sequelae including learning disabilities and hearing loss due to excessive neuroinflammation. There is a lack of efficacious compounds for adjuvant therapy to control this long-term consequence of PM. One hallmark is the recruitment of leukocytes to the brain to combat the bacterial spread. However, this process induces excessive inflammation, causing neuronal injury. Maraviroc (MVC)-a CCR5 antagonist-was demonstrated to inhibit leukocyte recruitment and attenuate neuroinflammation in several inflammatory diseases. Here, we show that in vitro, MVC decreased nitric oxide production in astroglial cells upon pneumococcal stimulation. In vivo, infant Wistar rats were infected with 1 × 104 CFU/ml S. pneumoniae and randomized for treatment with ceftriaxone plus MVC (100 mg/kg) or ceftriaxone monotherapy. During the acute phase, neuroinflammation in the CSF was measured and histopathological analyses were performed to determine neuronal injury. Long-term neurofunctional outcome (learning/memory and hearing capacity) after PM was assessed. MVC treatment reduced hippocampal cell apoptosis but did not affect CSF neuroinflammation and the neurofunctional outcome after PM. We conclude that MVC treatment only exerted limited effect on the pathophysiology of PM and is, therefore, not sufficiently beneficial in this experimental paradigm of PM.


Assuntos
Meningite Pneumocócica , Animais , Ceftriaxona , Humanos , Maraviroc/farmacologia , Meningite Pneumocócica/tratamento farmacológico , Meningite Pneumocócica/microbiologia , Neuroproteção , Ratos , Ratos Wistar , Receptores CCR5
9.
J Virol ; 96(14): e0185121, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35862673

RESUMO

A rare but natural polymorphism in the HIV-1 envelope (Env) glycoprotein, lysine at position 425 was selected as a mutation conferring resistance to maraviroc (MVC) in vitro. N425K has not been identified in HIV-infected individuals failing an MVC-based treatment. This study reports that the rare K425 polymorphism in an HIV-1 subtype A Env has increased affinity for CD4, resulting in faster host cell entry kinetics and the ability to scavenge for low cell surface expression of CD4 to mediate entry. Whereas the subtype A wild-type isolate-74 Env (N425) is inhibited by soluble (s) CD4, HIV-1 with K425 A74 Env shows enhanced infection and the ability to infect CCR5+ cells when pretreated with sCD4. Upon adding K425 or N425 HIV-1 to CD4+/CCR5+ cells along with RANTES/CCL3, only K425 HIV-1 was able to infect cells when CCR5 recycled/returned to the cell surface at 12 h post-treatment. These findings suggest that upon binding to CD4, K425 Env may maintain a stable State 2 "open" conformation capable of engaging CCR5 for entry. Only K425 was significantly more sensitivity than wild-type N425 A74 to inhibition by the CD4 binding site (bs) compound, BMS-806, the CD4bs antibody, VRC01 and N6, and the single-chain CD4i antibody, SCm9. K425 A74 was also capable of activating B cells expressing the VRC01 surface immunoglobulin. In summary, despite increased replicative fitness, we propose that K425 HIV-1 may be counterselected within infected individuals if K425 HIV-1 is rapidly eliminated by CD4bs-neutralizing antibodies. IMPORTANCE Typically, a natural amino acid polymorphism is found as the wild-type sequence in the HIV-1 population if it provides a selective advantage to the virus. The natural K425 polymorphism in HIV-1 Env results in higher host cell entry efficiency and greater replicative fitness by virtue of its high binding affinity to CD4. The studies presented herein suggest that the rare K425 HIV-1, compared to the common N425 HIV-1, may be more sensitive to inhibition by CD4bs-neutralizing antibodies (i.e., antibodies that bind to the CD4 binding pocket on the HIV-1 envelope glycoprotein). If CD4bs antibodies did emerge in an infected individual, the K425 HIV-1 may be hypersensitive to inhibition, and thus this K425 virus variant may be removed from the HIV-1 swarm despite its higher replication fitness. Studies are now underway to determine whether addition of the K425 polymorphism into the Envelope-based HIV-1 vaccines could enhance protective immunity.


Assuntos
Proteína gp120 do Envelope de HIV , HIV-1 , Internalização do Vírus , Anticorpos Neutralizantes/metabolismo , Sítios de Ligação , Antígenos CD4/metabolismo , Farmacorresistência Viral/genética , Anticorpos Anti-HIV/metabolismo , Proteína gp120 do Envelope de HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Maraviroc/farmacologia , Polimorfismo Genético , Ligação Proteica
10.
J Environ Manage ; 319: 115735, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35863307

RESUMO

In this study photochemical transformation of the antiretroviral pharmaceutical maraviroc under the simulated UV-Vis radiation was presented. The drug was shown to be extremely photo-resistant, with a half-life over 250 h, which is particularly significant, considering its presence in the aquatic environments. Addition of the natural river water matrix substantially increased the degradation rate, albeit the process led to formation of numerous phototransformation products. Due to high photostability and presumable environmental persistence of maraviroc, a photocatalytic method of its elimination was proposed. Although titanium dioxide alone presented acceptable results, its combination with peroxymonosulfate enormously accelerated the degradation process, increasing it over 67 000 times in comparison with the direct photolysis. Substitution of ultrapure water with river water resulted in inhibition of the PMS-driven processes, however the decomposition efficiency was still very high. Noteworthy, majority of the identified photoproducts were still present after termination of irradiation in all the experiments, which may indicate necessity of ecotoxicological assessment of those compounds.


Assuntos
Fármacos Anti-HIV , Poluentes Químicos da Água , Catálise , Cinética , Maraviroc , Peróxidos , Fotólise , Titânio/química , Água , Poluentes Químicos da Água/química
11.
Antimicrob Agents Chemother ; 66(8): e0060922, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35856680

RESUMO

Although current antiretroviral therapy (ART) has increased life expectancy, a cure for human immunodeficiency virus (HIV) remains elusive due to the persistence of the virus in tissue reservoirs. In the present study, we sought to elucidate the relationship between antiretrovirals (ARVs) and viral expression in the spleen. We performed mass spectrometry imaging (MSI) of 6 different ARVs, RNAscope in situ hybridization of viral RNA, and immunohistochemistry of three different fibrosis markers in the spleens of 8 uninfected and 10 reverse transcriptase simian-human immunodeficiency virus (RT-SHIV)-infected rhesus macaques (infected for 6 weeks) that had been dosed for 10 days with combination ART. Using MATLAB, computational quantitative imaging analysis was performed to evaluate the spatial and pharmacological relationships between the 6 ARVs, viral RNA, and fibrotic deposition. In these spleens, >50% of the spleen tissue area was not covered by any detectable ARV response (any concentration above the limits of detection for individual ARVs). The median spatial ARV coverage across all tissues was driven by maraviroc followed by efavirenz. Yet >50% of RNA-positive cells were not exposed to any detectable ARV. Quantifiable maraviroc and efavirenz colocalization with RNA-positive cells was usually greater than the in vitro concentration inhibiting 50% replication (IC50). Fibrosis markers covered more than 50% of the spleen tissue area and had negative relationships with cumulative ARV coverages. Our findings suggest that a heterogeneous ARV spatial distribution must be considered when evaluating viral persistence in lymphoid tissue reservoirs.


Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Fibrose , HIV/genética , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , Humanos , Macaca mulatta/genética , Macaca mulatta/metabolismo , Maraviroc/uso terapêutico , RNA Viral/genética , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/metabolismo , Baço/metabolismo , Carga Viral
12.
J Neuroinflammation ; 19(1): 195, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906621

RESUMO

BACKGROUND: Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear. METHODS: Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks. RESULTS: Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C-C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure. CONCLUSION: These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.


Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno do Espectro Autista/induzido quimicamente , Comportamento Animal , Modelos Animais de Doenças , Feminino , Maraviroc/uso terapêutico , Maraviroc/toxicidade , Camundongos , Minociclina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores CCR5/genética , Ácido Valproico/toxicidade
13.
AIDS Behav ; 26(12): 4107-4114, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35687192

RESUMO

HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ2 = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ2 = 9.36, p = 0.009 and χ2 = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Masculino , Feminino , Humanos , Emtricitabina/uso terapêutico , Tenofovir/uso terapêutico , Maraviroc/uso terapêutico , Homossexualidade Masculina , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Adesão à Medicação , Comportamento Sexual , Antirretrovirais/uso terapêutico
14.
Eur J Cancer ; 167: 112-122, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35427833

RESUMO

BACKGROUND: PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC. METHODS: Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu. RESULTS: The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was >70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS. CONCLUSIONS: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.


Assuntos
Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Inibidores de Checkpoint Imunológico , Maraviroc/uso terapêutico , Repetições de Microssatélites
15.
Int Immunopharmacol ; 108: 108755, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35395466

RESUMO

Neuroinflammation is a key factor that contributes to the secondary damage after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5 (CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC, APEXBIO, UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion (MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) injected with doses (20 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia cells were stimulated with doses of MVC (20 nM) for 12 h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after OGD/R. The expression of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in microglia was down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of these cytokines by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN, Beyotime, SC0132) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials. MVC has been widely used in HIV treatment which showed its safety. Based on its anti-inflammatory and anti-apoptotic mechanisms, we speculate that MVC may be a potential drug for treating ischemic stroke in future clinical trials.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Maraviroc , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/metabolismo , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/complicações , Inflamação/tratamento farmacológico , Maraviroc/farmacologia , Maraviroc/uso terapêutico , Camundongos , Microglia , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores CCR5 , Receptores de Quimiocinas/antagonistas & inibidores , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
16.
J Immunol ; 208(5): 1170-1179, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35140134

RESUMO

Mucosa-associated invariant T (MAIT) cells recognize bacterial riboflavin metabolite Ags presented by MHC class Ib-related protein (MR1) and play important roles in immune control of microbes that synthesize riboflavin. This includes the pathobiont Staphylococcus aureus, which can also express a range of virulence factors, including the secreted toxin leukocidin ED (LukED). In this study, we found that human MAIT cells are hypersensitive to LukED-mediated lysis and lost on exposure to the toxin, leaving a T cell population devoid of MAIT cells. The cytolytic effect of LukED on MAIT cells was rapid and occurred at toxin concentrations lower than those required for toxicity against conventional T cells. Furthermore, this coincided with high MAIT cell expression of CCR5, and loss of these cells was efficiently inhibited by the CCR5 inhibitor maraviroc. Interestingly, exposure and preactivation of MAIT cells with IL-12 and IL-18, or activation via TCR triggering, partially protected from LukED toxicity. Furthermore, analysis of NK cells indicated that LukED targeted the mature cytotoxic CD57+ NK cell subset in a CCR5-independent manner. Overall, these results indicate that LukED efficiently eliminates immune cells that can respond rapidly to S. aureus in an innate fashion without the need for clonal expansion, and that MAIT cells are exceptionally vulnerable to this toxin. Thus, the findings support a model where LukED secretion may allow S. aureus to avoid recognition by the rapid cell-mediated responses mediated by MAIT cells and NK cells.


Assuntos
Evasão da Resposta Imune/imunologia , Células Matadoras Naturais/imunologia , Leucocidinas/metabolismo , Células T Invariantes Associadas à Mucosa/patologia , Receptores CCR5/metabolismo , Staphylococcus aureus/patogenicidade , Antagonistas dos Receptores CCR5/farmacologia , Linhagem Celular , Humanos , Subunidade p35 da Interleucina-12/metabolismo , Interleucina-18/metabolismo , Ativação Linfocitária/imunologia , Maraviroc/farmacologia , Células T Invariantes Associadas à Mucosa/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Células THP-1 , Fatores de Virulência/metabolismo
18.
J Allergy Clin Immunol ; 149(1): 113-124.e7, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146578

RESUMO

BACKGROUND: Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3-/-, and Ccr5-/- mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3-/- mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3-/- and Ccr5-/- mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma.


Assuntos
Asma/imunologia , Receptores CCR5/imunologia , Receptores CXCR3/imunologia , Adulto , Resistência das Vias Respiratórias , Animais , Asma/tratamento farmacológico , Asma/fisiopatologia , Brônquios/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Antagonistas dos Receptores CCR5/uso terapêutico , Feminino , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Interferon gama/imunologia , Masculino , Maraviroc/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Receptores CCR5/genética , Receptores CXCR3/genética , Mucosa Respiratória/imunologia , Índice de Gravidade de Doença , Adulto Jovem
20.
AIDS ; 36(1): 11-18, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34628442

RESUMO

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.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , Cicloexanos/farmacologia , Cicloexanos/uso terapêutico , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/tratamento farmacológico , Humanos , Maraviroc
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