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1.
Oncotarget ; 15: 355-359, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829647

RESUMO

Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Cardiotoxicidade , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Inibidores de Proteínas Quinases/efeitos adversos , Cardiotoxicidade/etiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/efeitos adversos , Medição de Risco , Pirimidinas/efeitos adversos , Pirazóis/efeitos adversos , Biomarcadores , Polimorfismo de Nucleotídeo Único , Canal de Potássio KCNQ1/genética
2.
Luminescence ; 39(6): e4792, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845344

RESUMO

Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA products to inhibit viral replication. While, adenine is a purine nucleobase that is found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to generate genetic information. For the first time, the binding mechanism between FVP and adenine was determined using different techniques, including UV-visible spectrophotometry, spectrofluorimetry, synchronous fluorescence (SF) spectroscopy, Fourier transform infrared (FTIR), fluorescence resonance energy transfer (FRET), and metal ion complexation. The fluorescence spectra indicated that FVP is bound to adenine via Van der Waals forces and hydrogen bonding through a spontaneous binding process (ΔGο < 0). The quenching mechanism was found to be static. Various temperature settings were used to investigate thermodynamic characteristics, such as binding forces, binding constants, and the number of binding sites. The reaction parameters, including the enthalpy change (ΔHο) and entropy change (ΔSο), were calculated using Van't Hoff's equation. The findings demonstrated that the adenine-FVP binding was endothermic. Furthermore, the results of the experiments revealed that some metal ions (K+, Ca+2, Co+2, Cu+2, and Al+3) might facilitate the binding interaction between FVP and adenine. Slight changes are observed in the FTIR spectra of adenine, indicating the binding interaction between adenine and FVP. This study may be useful in understanding the pharmacokinetic characteristics of FVP and how the drug binds to adenine to prevent any side effects.


Assuntos
Nucleotídeos de Adenina , Amidas , Antivirais , Pirazinas , Termodinâmica , Pirazinas/química , Pirazinas/metabolismo , Amidas/química , Amidas/metabolismo , Nucleotídeos de Adenina/química , Nucleotídeos de Adenina/metabolismo , Antivirais/química , Antivirais/farmacologia , Antivirais/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Espectrometria de Fluorescência , Transferência Ressonante de Energia de Fluorescência , Espectrofotometria Ultravioleta , Sítios de Ligação , Adenina/química , Adenina/metabolismo
3.
HIV Res Clin Pract ; 25(1): 2339576, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38831550

RESUMO

BACKGROUND: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. METHODS: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. RESULTS: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (-2.6% [95% CI: -5.1, -0.1%, p = .041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. CONCLUSIONS: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered.


Assuntos
Alanina , Infecções por HIV , Piridonas , Tenofovir , Aumento de Peso , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piridonas/uso terapêutico , Adulto , Alanina/uso terapêutico , Alanina/análogos & derivados , Aumento de Peso/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Carga Viral/efeitos dos fármacos , Substituição de Medicamentos , Aminobutiratos/uso terapêutico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/uso terapêutico , Triazóis
4.
BMC Infect Dis ; 24(1): 565, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844855

RESUMO

BACKGROUND: The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens. METHODS: In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG). RESULTS: The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events. CONCLUSIONS: BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).


Assuntos
Amidas , Fármacos Anti-HIV , Combinação de Medicamentos , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Profilaxia Pós-Exposição , Piridonas , Tenofovir , Humanos , Infecções por HIV/prevenção & controle , Estudos Prospectivos , Masculino , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , China , Adulto , Feminino , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Amidas/uso terapêutico , Amidas/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Pessoa de Meia-Idade , Profilaxia Pós-Exposição/métodos , Adesão à Medicação/estatística & dados numéricos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Alanina/uso terapêutico , Alanina/administração & dosagem , Adenina/análogos & derivados , Adenina/uso terapêutico , Adenina/administração & dosagem , Adulto Jovem , Piperazinas
5.
Front Immunol ; 15: 1390958, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38765016

RESUMO

This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Crioglobulinemia , Fator 88 de Diferenciação Mieloide , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/etiologia , Fator 88 de Diferenciação Mieloide/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pessoa de Meia-Idade , Masculino , Feminino , Adenina/análogos & derivados , Adenina/uso terapêutico , Idoso , Piperidinas/uso terapêutico , Resultado do Tratamento
6.
Astrobiology ; 24(5): 559-569, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38768432

RESUMO

Ultraviolet (UV) light is likely to have played important roles in surficial origins of life scenarios, potentially as a productive source of energy and molecular activation, as a selective means to remove unwanted side products, or as a destructive mechanism resulting in loss of molecules/biomolecules over time. The transmission of UV light through prebiotic waters depends upon the chemical constituents of such waters, but constraints on this transmission are limited. Here, we experimentally measure the molar decadic extinction coefficients for a number of small molecules used in various prebiotic synthetic schemes. We find that many small feedstock molecules absorb most at short (∼200 nm) wavelengths, with decreasing UV absorption at longer wavelengths. For comparison, we also measured the nucleobase adenine and found that adenine absorbs significantly more than the simpler molecules often invoked in prebiotic synthesis. Our results enable the calculation of UV photon penetration under varying chemical scenarios and allow further constraints on plausibility and self-consistency of such scenarios. While the precise path that prebiotic chemistry took remains elusive, improved understanding of the UV environment in prebiotically plausible waters can help constrain both the chemistry and the environmental conditions that may allow such chemistry to occur.


Assuntos
Planeta Terra , Origem da Vida , Raios Ultravioleta , Adenina/química , Prebióticos/análise , Água/química
8.
Lancet Oncol ; 25(6): 744-759, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821083

RESUMO

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Linfocítica Crônica de Células B , Piperidinas , Sulfonamidas , Vidarabina , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Seguimentos , Piperidinas/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Adenina/análogos & derivados , Adenina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Intervalo Livre de Progressão , Ciclofosfamida/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Imunoterapia , Adulto
9.
Front Biosci (Landmark Ed) ; 29(5): 201, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38812314

RESUMO

BACKGROUND: Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients. However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated. METHODS: We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF. Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells. Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups. To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation. RESULTS: About 2.67% of patients developed atrial arrhythmias after ibrutinib administration. HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls. Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib. Inhibiting autophagy upregulated Cx43 and Cx40. CONCLUSIONS: The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy. CLINICAL TRIAL REGISTRATION: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.


Assuntos
Adenina , Fibrilação Atrial , Autofagia , Conexina 43 , Conexinas , Fosfatidilinositol 3-Quinases , Piperidinas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/efeitos adversos , Serina-Treonina Quinases TOR/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piperidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Conexina 43/metabolismo , Conexina 43/genética , Feminino , Fibrilação Atrial/metabolismo , Fibrilação Atrial/induzido quimicamente , Conexinas/metabolismo , Conexinas/genética , Masculino , Idoso , Pessoa de Meia-Idade , Proteína alfa-5 de Junções Comunicantes , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/induzido quimicamente
10.
Int Immunopharmacol ; 134: 112222, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38728881

RESUMO

Cardiovascular disease is currently the number one cause of death endangering human health. There is currently a large body of research showing that the development of cardiovascular disease and its complications is often accompanied by inflammatory processes. In recent years, epitranscriptional modifications have been shown to be involved in regulating the pathophysiological development of inflammation in cardiovascular diseases, with 6-methyladenine being one of the most common RNA transcriptional modifications. In this review, we link different cardiovascular diseases, including atherosclerosis, heart failure, myocardial infarction, and myocardial ischemia-reperfusion, with inflammation and describe the regulatory processes involved in RNA methylation. Advances in RNA methylation research have revealed the close relationship between the regulation of transcriptome modifications and inflammation in cardiovascular diseases and brought potential therapeutic targets for disease diagnosis and treatment. At the same time, we also discussed different cell aspects. In addition, in the article we also describe the different application aspects and clinical pathways of RNA methylation therapy. In summary, this article reviews the mechanism, regulation and disease treatment effects of m6A modification on inflammation and inflammatory cells in cardiovascular diseases in recent years. We will discuss issues facing the field and new opportunities that may be the focus of future research.


Assuntos
Doenças Cardiovasculares , Epigênese Genética , Inflamação , Humanos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Inflamação/genética , Animais , Adenina/análogos & derivados , Transcriptoma , Metilação
12.
AIDS Res Ther ; 21(1): 34, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773606

RESUMO

INTRODUCTION: Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. METHODS: A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. RESULTS: Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. CONCLUSIONS: In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.


Assuntos
Adenina , Alanina , Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Falência Renal Crônica , Oxazinas , Diálise Peritoneal , Piperazinas , Piridonas , Tenofovir , Humanos , Masculino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/farmacocinética , Piridonas/farmacocinética , Pessoa de Meia-Idade , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Piperazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Alanina/farmacocinética , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Falência Renal Crônica/terapia
13.
Lancet ; 403(10441): 2293-2306, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38705160

RESUMO

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.


Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Linfoma de Célula do Manto , Piperidinas , Rituximab , Transplante Autólogo , Vincristina , Humanos , Linfoma de Célula do Manto/terapia , Linfoma de Célula do Manto/tratamento farmacológico , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Pessoa de Meia-Idade , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Adulto , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Idoso , Europa (Continente) , Transplante de Células-Tronco Hematopoéticas/métodos , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Doxorrubicina/administração & dosagem , Adulto Jovem , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Adolescente , Israel , Resultado do Tratamento
14.
Int J Mol Sci ; 25(10)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38791284

RESUMO

Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Adenina/análogos & derivados , Fosfolipase C gama/metabolismo , Fosfolipase C gama/genética , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Mutação
15.
AAPS PharmSciTech ; 25(5): 123, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816624

RESUMO

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25 mg Film Tablet", which contains 25 mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.


Assuntos
Alanina , Disponibilidade Biológica , Estudos Cross-Over , Comprimidos , Tenofovir , Equivalência Terapêutica , Tenofovir/farmacocinética , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Humanos , Projetos Piloto , Alanina/farmacocinética , Alanina/química , Adulto , Masculino , Administração Oral , Adulto Jovem , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/administração & dosagem , Pró-Fármacos/farmacocinética , Pró-Fármacos/administração & dosagem
16.
Turk J Haematol ; 41(2): 91-96, 2024 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-38721568

RESUMO

Objective: Bruton tyrosine kinase inhibition in cardiac tissue causes inhibition of the PI3K-AKT signaling pathway, which is responsible for protecting cardiac tissue during stress. Therefore, there is an increase in the risk of arrhythmia. This study explores the prediction of that risk with the Age-Creatinine-Ejection Fraction (ACEF) score as a simple scoring system based on the components of age, creatinine, and ejection fraction. Materials and Methods: Patients diagnosed with chronic lymphocytic leukemia (CLL) and receiving ibrutinib treatment for at least 1 year were evaluated with echocardiography and Holter electrocardiography and the results were compared with a control group of CLL patients who had not received treatment. ACEF score was calculated with the formula age/left ventricular ejection fraction+1 (if creatinine >2.0 mg/dL). Results: When the arrhythmia development of the patients was evaluated, no statistically significant difference was found between the control and ibrutinib groups in terms of types of arrhythmias other than paroxysmal atrial fibrillation (PAF). PAF was found to occur at rates of 8% versus 22% (p=0.042) among ibrutinib non-users versus users. For patients using ibrutinib, an ACEF score of >1.21 predicted the development of PAF with 77% sensitivity and 75% specificity (area under the curve: 0.830, 95% confidence interval: 0.698-0.962, p<0.001). Conclusion: The ACEF score can be used as a risk score that predicts the development of PAF in patients diagnosed with CLL who are scheduled to start ibrutinib.


Assuntos
Adenina , Arritmias Cardíacas , Leucemia Linfocítica Crônica de Células B , Piperidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Adenina/análogos & derivados , Adenina/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Creatinina/sangue , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Idoso de 80 Anos ou mais , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
17.
Expert Rev Hematol ; 17(6): 201-210, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38784995

RESUMO

INTRODUCTION: This review evaluates zanubrutinib as a treatment option for adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Zanubrutinib, a covalent BTK (Bruton's tyrosine kinase) inhibitor, was recently approved by the US FDA based in part on head-to-head data demonstrating improved efficacy and safety compared to ibrutinib. AREAS COVERED: The review discusses the efficacy, safety, and comparative advantages of zanubrutinib, highlighting its safety profile compared to other BTK inhibitors. It also addresses the unmet needs of current therapies in CLL/SLL and provides an overview of competitor compounds and ongoing research in BTK inhibition. EXPERT OPINION: Zanubrutinib, the first BTK inhibitor to demonstrate superior efficacy and safety compared to another BTK inhibitor in CLL, is likely to be widely adopted due to its high-quality data and ease of use. Looking ahead, pirtobrutinib, a novel non-covalent BTK inhibitor, has shown promise in heavily pretreated CLL patients, including those unresponsive to covalent inhibitors, with ongoing phase 3 trials comparing it against ibrutinib. The field is also exploring time-limited therapies like the combination of ibrutinib and venetoclax, with ongoing trials evaluating different combinations to optimize efficacy and minimize toxicity, indicating a promising future for combination therapies in CLL treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Piperidinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Sulfonamidas/uso terapêutico , Antineoplásicos/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Resultado do Tratamento , Ensaios Clínicos como Assunto
18.
Lancet HIV ; 11(6): e357-e368, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734016

RESUMO

BACKGROUND: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1. METHODS: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791. FINDINGS: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per µL) and total lymphocyte counts (mean change -0·20 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.


Assuntos
Adenina , Alanina , Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , HIV-1 , Compostos Heterocíclicos de 4 ou mais Anéis , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Feminino , Masculino , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Adulto , Emtricitabina/administração & dosagem , Emtricitabina/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Método Duplo-Cego , Piridonas/administração & dosagem , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Pessoa de Meia-Idade , Alanina/administração & dosagem , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Piperazinas/administração & dosagem , Amidas/administração & dosagem , Carga Viral/efeitos dos fármacos , Resultado do Tratamento , Esquema de Medicação , Desoxiadenosinas , Triazóis
19.
ACS Appl Mater Interfaces ; 16(22): 29235-29247, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38769743

RESUMO

Expanding the functions and applications of DNA by integrating noncanonical bases and structures into biopolymers is a continuous scientific effort. An adenine-rich strand (A-strand) is introduced as functional scaffold revealing, in the presence of the low-molecular-weight cofactor cyanuric acid (CA, pKa 6.9), supramolecular hydrogel-forming efficacies demonstrating multiple pH-responsiveness. At pH 1.2, the A-strand transforms into a parallel A-motif duplex hydrogel cross-linked by AH+-H+A units due to the protonation of adenine (pKa 3.5). At pH 5.2, and in the presence of coadded CA, a helicene-like configuration is formed between adenine and protonated CA, generating a parallel A-CA triplex cross-linked hydrogel. At pH 8.0, the hydrogel undergoes transition into a liquid state by deprotonation of CA cofactor units and disassembly of A-CA triplex into its constituent components. Density functional theory calculations and molecular dynamics simulations, supporting the structural reconfigurations of A-strand in the presence of CA, are performed. The sequential pH-stimulated hydrogel states are rheometrically characterized. The hydrogel framework is loaded with fluorescein-labeled insulin, and the pH-stimulated release of insulin from the hydrogel across the pH barriers present in the gastrointestinal tract is demonstrated. The results provide principles for future application of the hydrogel for oral insulin administration for diabetes.


Assuntos
Adenina , DNA , Hidrogéis , Triazinas , Hidrogéis/química , Concentração de Íons de Hidrogênio , DNA/química , Adenina/química , Triazinas/química , Simulação de Dinâmica Molecular , Insulina/química
20.
Int J Biol Macromol ; 270(Pt 1): 132289, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38735607

RESUMO

S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep). X-ray crystallography, isothermal titration calorimetry (ITC), and molecular docking were used to elucidate the binding mechanisms of Lpg2021 to its substrates and inhibitors. Virtual screening was performed to identify potential Lpg2021 inhibitors. This study contributes a novel perspective to the understanding of SAHH evolution and establishes a structural framework for designing specific inhibitors targeting pathogenic Legionella pneumophila SAHH.


Assuntos
Adenosil-Homocisteinase , Legionella pneumophila , Simulação de Acoplamento Molecular , Legionella pneumophila/enzimologia , Especificidade por Substrato , Adenosil-Homocisteinase/metabolismo , Adenosil-Homocisteinase/antagonistas & inibidores , Adenosil-Homocisteinase/química , Cristalografia por Raios X , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/química , Adenina/química , Adenina/metabolismo , Adenina/análogos & derivados , Ligação Proteica , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , N-Glicosil Hidrolases
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