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1.
Nucleic Acids Res ; 52(1): 4-21, 2024 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-37993417

RESUMEN

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.


Cancer cells driven by runaway transcription factor networks frequently depend on the cellular machinery that promotes DNA accessibility. For this reason, recently developed small molecules that impair SWI/SNF (or BAF) chromatin remodeling activity have been under active evaluation as anti-cancer agents. However, exactly when SWI/SNF activity is essential in dependent cancers has remained unknown. By combining live-cell imaging and genome-wide profiling in neuroblastoma cells, Cermakova et al. discover that SWI/SNF activity is needed for survival only during G1 phase of the cell cycle. The authors reveal that in several cancer settings, dependency on SWI/SNF arises from the need to reactivate factors involved in G1-S transition. Because of this role, authors find that SWI/SNF inhibition potentiates cell-cycle exit by retinoic acid.


Asunto(s)
Fase G1 , Neoplasias , Factores de Transcripción , Humanos , Ciclo Celular , Cromatina/genética , Ensamble y Desensamble de Cromatina , ADN , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/metabolismo , Elementos de Facilitación Genéticos
2.
Beilstein J Org Chem ; 20: 1029-1036, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38746653

RESUMEN

The RNA-dependent RNA polymerase (RdRp) represents a prominent target in the discovery and development of new antivirotics against RNA viruses, inhibiting the replication process. One of the most targeted RNA viruses of the last years is, without doubt, SARS-CoV-2, the cause of the recent COVID-19 pandemic. HeE1-2Tyr, a known inhibitor of flaviviral RdRp, has been discovered to also have antiviral potency against this coronavirus. In this study, we report three distinct modifications of HeE1-2Tyr: conversion of the core from a benzothiazole to a benzoxazole moiety and two different scaffold simplifications, respectively. We provide a novel synthetic approach and, in addition, evaluate the final molecules in an in vitro polymerase assay for biological activity.

3.
Electrophoresis ; 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38059733

RESUMEN

Cyclic dinucleotides (CDNs) are important second messengers in bacteria and eukaryotes. Detailed characterization of their physicochemical properties is a prerequisite for understanding their biological functions. Herein, we examine acid-base and electromigration properties of selected CDNs employing capillary electrophoresis (CE), density functional theory (DFT), and nuclear magnetic resonance (NMR) spectroscopy to provide benchmark pKa values, as well as to unambiguously determine the protonation sites. Acidity constants (pKa ) of the NH+ moieties of adenine and guanine bases and actual and limiting ionic mobilities of CDNs were determined by nonlinear regression analysis of the pH dependence of their effective electrophoretic mobilities measured by CE in aqueous background electrolytes in a wide pH range (0.98-11.48), at constant temperature (25°C), and constant ionic strength (25 mM). The thermodynamic pKa values were found to be in the range 3.31-4.56 for adenine and 2.28-3.61 for guanine bases, whereas the pKa of enol group of guanine base was in the range 10.21-10.40. Except for systematic shifts of ∼2 pKa , the pKa values calculated by the DFT-D3//COSMO-RS composite protocol that included large-scale conformational sampling and "cross-morphing" were in a relatively good agreement with the pKa s determined by CE and predict N1 atom of adenine and N7 atom of guanine as the protonation sites. The protonation of the N1 atom of adenine and N7 atom of guanine in acidic background electrolytes (BGEs) and the dissociation of the enol group of guanine in alkaline BGEs was confirmed also by NMR spectroscopy.

4.
Bioorg Med Chem Lett ; 76: 129010, 2022 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-36184029

RESUMEN

Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.


Asunto(s)
1-Fosfatidilinositol 4-Quinasa , Adenosina Trifosfato , 1-Fosfatidilinositol 4-Quinasa/química , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Ligandos , Adenosina Trifosfato/metabolismo , Adenina , Relación Estructura-Actividad , Diseño de Fármacos , Simulación del Acoplamiento Molecular
5.
Angew Chem Int Ed Engl ; 60(18): 10172-10178, 2021 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-33616279

RESUMEN

STING (stimulator of interferon genes) is a key regulator of innate immunity that has recently been recognized as a promising drug target. STING is activated by cyclic dinucleotides (CDNs) which eventually leads to expression of type I interferons and other cytokines. Factors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs-three pairs of natural (ribo) and fluorinated (2'-fluororibo) 3',3'-CDNs. X-ray structural analyses of six {STING:CDN} complexes did not offer any explanation for the different affinities of the studied ligands. ITC showed entropy/enthalpy compensation up to 25 kcal mol-1 for this set of similar ligands. The higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropy upon binding and by smaller strain (free) energy.


Asunto(s)
Proteínas de la Membrana/química , Nucleótidos Cíclicos/química , Sitios de Unión , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular
6.
J Mol Recognit ; 33(8): e2842, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32212222

RESUMEN

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin-dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics-based scoring was used to rationalize the affinities. In conclusion, the discovered 9-hydroxymethylnorbornyl moiety was shown by joint experimental-theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.


Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Norbornanos/farmacología , Nucleósidos/análogos & derivados , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 30(4): 126897, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31882298

RESUMEN

The nucleoside/nucleotide derived antiviral agents have been the most important components of antiviral therapy used in clinics. Recently, the focus of the medicinal chemists within this exciting research field has been affected mainly by the lack of effective therapies for the Hepatitis C virus (HCV) infection and several other "neglected" diseases caused by viruses such as Zika or Dengue. 2'-Methyl modified nucleosides and their monophosphate prodrugs (ProTides) have revolutionized the therapies for HCV in the last few years and, according to the latest research efforts, have also brought a promise for treatment of diseases caused by other members of Flaviviridae family. Here, we report on the design and synthesis of 5'-N and S modified ProTides derived from 2'-methyladenosine. We studied potential applicability of these derivatives as prodrugs of this archetypal antiviral compound.


Asunto(s)
Antivirales/química , Nucleótidos/química , Profármacos/química , Adenosina/análogos & derivados , Adenosina/química , Antivirales/síntesis química , Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Nitrógeno/química , Nucleótidos/metabolismo , Nucleótidos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Azufre/química , Virus Zika/efectos de los fármacos
8.
J Lipid Res ; 60(3): 683-693, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30626625

RESUMEN

The minor phospholipid, phosphatidylinositol 4-phosphate (PI4P), is emerging as a key regulator of lipid transfer in ER-membrane contact sites. Four different phosphatidylinositol 4-kinase (PI4K) enzymes generate PI4P in different membrane compartments supporting distinct cellular processes, many of which are crucial for the maintenance of cellular integrity but also hijacked by intracellular pathogens. While type III PI4Ks have been targeted by small molecular inhibitors, thus helping decipher their importance in cellular physiology, no inhibitors are available for the type II PI4Ks, which hinders investigations into their cellular functions. Here, we describe the identification of small molecular inhibitors of PI4K type II alpha (PI4K2A) by implementing a large scale small molecule high-throughput screening. A novel assay was developed that allows testing of selected inhibitors against PI4K2A in intact cells using a bioluminescence resonance energy transfer approach adapted to plate readers. The compounds disclosed here will pave the way to the optimization of PI4K2A inhibitors that can be used in cellular and animal studies to better understand the role of this enzyme in both normal and pathological states.


Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , 1-Fosfatidilinositol 4-Quinasa/química , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Animales , Transporte Biológico , Células COS , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Inhibidores Enzimáticos/metabolismo , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/metabolismo , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Conformación Proteica
9.
J Virol ; 91(21)2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28814513

RESUMEN

Tick-borne encephalitis virus (TBEV) causes a severe and potentially fatal neuroinfection in humans. Despite its high medical relevance, no specific antiviral therapy is currently available. Here we demonstrate that treatment with a nucleoside analog, 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), substantially improved disease outcomes, increased survival, and reduced signs of neuroinfection and viral titers in the brains of mice infected with a lethal dose of TBEV. To investigate the mechanism of action of 7-deaza-2'-CMA, two drug-resistant TBEV clones were generated and characterized. The two clones shared a signature amino acid substitution, S603T, in the viral NS5 RNA-dependent RNA polymerase (RdRp) domain. This mutation conferred resistance to various 2'-C-methylated nucleoside derivatives, but no cross-resistance was seen with other nucleoside analogs, such as 4'-C-azidocytidine and 2'-deoxy-2'-beta-hydroxy-4'-azidocytidine (RO-9187). All-atom molecular dynamics simulations revealed that the S603T RdRp mutant repels a water molecule that coordinates the position of a metal ion cofactor as 2'-C-methylated nucleoside analogs approach the active site. To investigate its phenotype, the S603T mutation was introduced into a recombinant TBEV strain (Oshima-IC) generated from an infectious cDNA clone and into a TBEV replicon that expresses a reporter luciferase gene (Oshima-REP-luc2A). The mutants were replication impaired, showing reduced growth and a small plaque size in mammalian cell culture and reduced levels of neuroinvasiveness and neurovirulence in rodent models. These results indicate that TBEV resistance to 2'-C-methylated nucleoside inhibitors is conferred by a single conservative mutation that causes a subtle atomic effect within the active site of the viral NS5 RdRp and is associated with strong attenuation of the virus.IMPORTANCE This study found that the nucleoside analog 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA) has high antiviral activity against tick-borne encephalitis virus (TBEV), a pathogen that causes severe human neuroinfections in large areas of Europe and Asia and for which there is currently no specific therapy. Treating mice infected with a lethal dose of TBEV with 7-deaza-2'-CMA resulted in significantly higher survival rates and reduced the severity of neurological signs of the disease. Thus, this compound shows promise for further development as an anti-TBEV drug. It is important to generate drug-resistant mutants to understand how the drug works and to develop guidelines for patient treatment. We generated TBEV mutants that were resistant not only to 7-deaza-2'-CMA but also to a broad range of other 2'-C-methylated antiviral medications. Our findings suggest that combination therapy may be used to improve treatment and reduce the emergence of drug-resistant viruses during nucleoside analog therapy for TBEV infection.

10.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 7): 1555-63, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26143926

RESUMEN

Phosphatidylinositol 4-phosphate (PI4P) is the most abundant monophosphoinositide in eukaryotic cells. Humans have four phosphatidylinositol 4-kinases (PI4Ks) that synthesize PI4P, among which are PI4K IIß and PI4K IIα. In this study, two crystal structures are presented: the structure of human PI4K IIß and the structure of PI4K IIα containing a nucleoside analogue. The former, a complex with ATP, is the first high-resolution (1.9 Å) structure of a PI4K. These structures reveal new details such as high conformational heterogeneity of the lateral hydrophobic pocket of the C-lobe and together provide a structural basis for isoform-specific inhibitor design.


Asunto(s)
1-Fosfatidilinositol 4-Quinasa/química , Diseño de Fármacos , Nucleósidos/química , Inhibidores de Proteínas Quinasas/química , 1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Adenosina Trifosfato/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Nucleósidos/farmacología , Conformación Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología
11.
Org Biomol Chem ; 13(9): 2703-15, 2015 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-25594585

RESUMEN

We describe here the preparation of conformationally locked cyclohexane nucleic acids designed as hybrids between locked nucleic acids (LNAs) and cyclohexene nucleic acids (CeNAs), both of which excel in hybridization with complementary RNAs. We have accomplished the synthesis of these adenine derivatives starting from a simple ketoester and installed all four chiral centres by means of total synthesis. The acquired monomers were incorporated into nonamer oligonucleotides.


Asunto(s)
Adenosina/química , Ciclohexanos/síntesis química , Ácidos Nucleicos/síntesis química , Adenosina/síntesis química , Ciclohexanos/química , Estructura Molecular , Ácidos Nucleicos/química
12.
Bioorg Med Chem ; 23(1): 184-91, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25435471

RESUMEN

We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel.


Asunto(s)
Antivirales/síntesis química , Norbornanos/química , Nucleósidos/química , Nucleótidos/química , Humanos , Norbornanos/síntesis química , Conformación de Ácido Nucleico , Nucleósidos/síntesis química , Nucleótidos/síntesis química , Estereoisomerismo
13.
Bioorg Med Chem ; 22(11): 2974-83, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24775916

RESUMEN

A synthetic route toward a series of unique cyclic nucleoside phosphonates locked in South conformation is described. The desired conformation is stabilized by a substitution of the sugar moiety by bicyclo[2.2.1]heptane (norbornane) bearing a purine or pyrimidine nucleobase in the bridgehead position. Although the final phosphonate derivatives are devoid of any significant antiviral activity probably due to the unfavorable conformational properties, several intermediates and their analogs exhibit surprising activity against feline herpes virus. Since these compounds do not possess an appropriate hydroxymethyl function allowing phosphorylation and subsequent incorporation into the polynucleotide chain, it seems to be likely that these compounds act by a novel unknown mechanism of action and may represent a new possible alternative for nucleoside and nucleotide therapeutics of this widely spread feline infection. A number of derivatives exerted also a significant antiviral activity against Coxsackievirus B3 and B4.


Asunto(s)
Antivirales/farmacología , Calicivirus Felino/efectos de los fármacos , Norbornanos/farmacología , Nucleótidos/farmacología , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Norbornanos/síntesis química , Norbornanos/química , Nucleótidos/síntesis química , Nucleótidos/química , Relación Estructura-Actividad
14.
Arch Pharm (Weinheim) ; 347(7): 478-85, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24652670

RESUMEN

The synthesis of a novel library of purine derivatives bearing various bicyclic and polycylic substituents at the N-9 position is described. The series includes norbornanes, bicyclo[2.2.2]octanes, and bicyclo[3.2.1]octanes attached at the bridgehead position as well as bicyclo[3.1.1]heptanes, tetrahydro-1-naphthalenes, and adamantanes bonded either directly or via a linear chain to the 6-chloropurine nucleobase. A number of prepared derivatives exerted significant activity against the enterovirus. Despite attempts to correlate the activity against picornaviruses with their phosphatidylinositol 4-kinase KIIIß inhibitory activity, it is clear that the inhibition of this host factor cannot explain the observed antiviral potency.


Asunto(s)
Antivirales/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Enterovirus/efectos de los fármacos , Norbornanos/síntesis química , Purinas/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Antivirales/toxicidad , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Efecto Citopatogénico Viral , Enterovirus/fisiología , Estructura Molecular , Norbornanos/química , Norbornanos/farmacología , Norbornanos/toxicidad , Purinas/química , Purinas/farmacología , Purinas/toxicidad , Replicación Viral/efectos de los fármacos
15.
J Struct Biol X ; 10: 100109, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39188530

RESUMEN

Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses. In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA. This capping is crucial for efficient viral RNA translation, stability, and immune evasion. Our previous research identified nsp14 inhibitors based on the chemical scaffold of its methyl donor - the S-adenosyl methionine (SAM) - featuring a modified adenine base and a substituted arylsulfonamide. However, the binding mode of these inhibitors was based only on docking experiments. To uncover atomic details of nsp14 inhibition we solved the crystal structure of nsp14 bound to STM957. The structure revealed the atomic details of nsp14 inhibition such that the 7-deaza-adenine moiety of STM957 forms specific interactions with Tyr368, Ala353, and Phe367, while the arylsulfonamide moiety engages with Asn388 and Phe506. The large aromatic substituent at the 7-deaza position displaces a network of water molecules near the adenine base. Surprisingly, this was recently observed in the case of an unrelated monkeypox MTase VP39, where the 7-deaza modified SAH analogs also displaced water molecules from the vicinity of the active site.

16.
Structure ; 32(4): 433-439.e4, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38325369

RESUMEN

The cGAS-STING pathway is a crucial part of innate immunity; it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability and their affinity for STING. These compounds demonstrated exceptional activity against STING. Despite their distinct chemical modifications relative to the canonical cyclic dinucleotides (CDNs), crystallographic analysis revealed a binding mode with STING that was consistent with the canonical CDNs. Importantly, MDs were resistant to cleavage by viral poxin nucleases and MDs-bound poxin adopted an unliganded-like conformation. Moreover, MDs complexed with poxin showed a conformation distinct from cGAMP bound to poxin, closely resembling their conformation when bound to STING. In conclusion, the development of MD1203 and MD1202D showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation-a crucial characteristic for future development of antivirals.


Asunto(s)
Neoplasias , Nucleótidos Cíclicos , Humanos , Nucleótidos Cíclicos/química , Nucleótidos Cíclicos/metabolismo , Nucleotidiltransferasas/química , Inmunidad Innata
17.
RSC Med Chem ; 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39220762

RESUMEN

The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5'-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5'-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound 18l (HK370) demonstrated high selectivity and favorable in vitro pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.

18.
Org Biomol Chem ; 11(34): 5702-13, 2013 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-23884430

RESUMEN

The non-hydrolyzable alkylcarbonate analogs of O-acetyl-ADP-ribose have been synthesized from the phosphorylated ribose derivatives after coupling with AMP morpholidate promoted by mechanical grinding. The analogs were assessed for their ability to inhibit the human sirtuin homolog SIRT1.


Asunto(s)
Carbonatos/química , O-Acetil-ADP-Ribosa/análogos & derivados , O-Acetil-ADP-Ribosa/síntesis química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Conformación Molecular , O-Acetil-ADP-Ribosa/química , O-Acetil-ADP-Ribosa/farmacología , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/metabolismo , Relación Estructura-Actividad
19.
ACS Infect Dis ; 9(1): 23-32, 2023 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-36472628

RESUMEN

Chronic hepatitis B (CHB) remains a major public health problem worldwide, with limited treatment options, but inducing an antiviral response by innate immunity activation may provide a therapeutic alternative. We assessed the cytokine-mediated anti-hepatitis B virus (HBV) potential for stimulating the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway using STING agonists in primary human hepatocytes (PHH) and nonparenchymal liver cells (NPCs). The natural STING agonist, 2',3'-cyclic GMP-AMP, the synthetic analogue 3',3'-c-di(2'F,2'dAMP), and its bis(pivaloyloxymethyl) prodrug had strong indirect cytokine-mediated anti-HBV effects in PHH regardless of HBV genotype. Furthermore, STING agonists induced anti-HBV cytokine secretion in vitro, in both human and mouse NPCs, and triggered hepatic T cell activation. Cytokine secretion and lymphocyte activation were equally stimulated in NPCs isolated from control and HBV-persistent mice. Therefore, STING agonists modulate immune activation regardless of HBV persistence, paving the way toward a CHB therapy.


Asunto(s)
Hepatitis B , Herpesvirus Cercopitecino 1 , Humanos , Animales , Ratones , Citocinas/metabolismo , Hepatocitos , Hepatitis B/tratamiento farmacológico , Interferones/metabolismo
20.
Eur J Med Chem ; 259: 115685, 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37567057

RESUMEN

Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.


Asunto(s)
Neoplasias , Nucleótidos Cíclicos , Animales , Ratones , Nucleótidos Cíclicos/farmacología , Nucleótidos Cíclicos/metabolismo , ADN , Neoplasias/tratamiento farmacológico , Inmunoterapia , Inmunidad Innata
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