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1.
Nat Commun ; 12(1): 1517, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750821

RESUMEN

Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.


Asunto(s)
Antivirales/farmacología , Reposicionamiento de Medicamentos , Péptidos/farmacología , Internalización del Virus/efectos de los fármacos , Animales , Chlorocebus aethiops , Cloroquina/farmacología , Descubrimiento de Drogas , Femenino , Células HEK293 , Humanos , Indoles/farmacología , Ratones , Ratones Endogámicos BALB C , Serina Endopeptidasas/metabolismo , Células Vero
2.
Cell Death Dis ; 12(4): 310, 2021 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-33762578

RESUMEN

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.


Asunto(s)
/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Adulto , Anciano , Animales , Antivirales/farmacología , /metabolismo , Chlorocebus aethiops , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Femenino , Humanos , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Ubiquitina-Proteína Ligasas Nedd4/genética , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , /metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Células Vero
3.
Viruses ; 13(2)2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670363

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.


Asunto(s)
Antivirales/farmacología , Berberina/farmacología , Indoles/farmacología , Pirroles/farmacología , Replicación Viral/efectos de los fármacos , Adolescente , Animales , Células Cultivadas , Chlorocebus aethiops , Células Epiteliales/virología , Humanos , Masculino , ARN Viral/genética , Células Vero
4.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33576441

RESUMEN

Coronavirus disease 2019 (COVID­19) is an acute infectious pneumonia caused by a novel type of coronavirus infection. There are currently no clinically available specific drugs for the treatment of this virus. The process of host invasion is the key to viral infection, and it is a mechanism that needs to be considered when exploring antiviral drugs. At present, studies have confirmed that angiotensin­converting enzyme II (ACE2) is the main functional receptor through which severe acute respiratory syndrome coronavirus (SARS­CoV­2) invades host cells. Therefore, a number of studies have focused on this field. However, as ACE2 may play a dual role in mediating susceptibility and immunity to SARS­CoV­2 infection, the role of ACE2 in viral infection is controversial. Beginning with the physiological function of ACE2, the present review article summarizes the influence of the ACE2 content on the susceptibility to the virus and acute lung injury. Drug mechanisms were taken as the starting point, combined with the results of clinical trials, specifically elaborating upon and analyzing the efficacy of several ACE2­centered therapeutic drugs and their potential effects. In addition, the current status of ACE2 as a targeted therapy for COVID­19 is discussed in order to provide new insight into the clinical prevention and treatment of COVID­19.


Asunto(s)
/fisiología , Antivirales/farmacología , /terapia , Interacciones Huésped-Patógeno/fisiología , /antagonistas & inhibidores , /virología , Enfermedades Cardiovasculares/etiología , Cloroquina/análogos & derivados , Cloroquina/farmacología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Indoles/farmacología , Terapia Molecular Dirigida , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus
5.
Nat Commun ; 12(1): 896, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563994

RESUMEN

Histone phosphorylation is a ubiquitous post-translational modification that allows eukaryotic cells to rapidly respond to environmental stimuli. Despite correlative evidence linking histone phosphorylation to changes in gene expression, establishing the causal role of this key epigenomic modification at diverse loci within native chromatin has been hampered by a lack of technologies enabling robust, locus-specific deposition of endogenous histone phosphorylation. To address this technological gap, here we build a programmable chromatin kinase, called dCas9-dMSK1, by directly fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase. Targeting dCas9-dMSK1 to human promoters results in increased target histone phosphorylation and gene activation and demonstrates that hyperphosphorylation of histone H3 serine 28 (H3S28ph) in particular plays a causal role in the transactivation of human promoters. In addition, we uncover mediators of resistance to the BRAF V600E inhibitor PLX-4720 in human melanoma cells using genome-scale screening with dCas9-dMSK1. Collectively, our findings enable a facile way to reshape human chromatin using CRISPR/Cas9-based epigenome editing and further define the causal link between histone phosphorylation and human gene activation.


Asunto(s)
Sistemas CRISPR-Cas , Epigenómica/métodos , Histonas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Acetilación , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Línea Celular Tumoral , Cromatina/genética , Resistencia a Antineoplásicos/genética , Humanos , Indoles/farmacología , Fosforilación , Regiones Promotoras Genéticas/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Sulfonamidas/farmacología , Activación Transcripcional
6.
ACS Appl Mater Interfaces ; 13(7): 8026-8041, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33577301

RESUMEN

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.


Asunto(s)
Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Inmunoterapia , Metformina/farmacología , Fotoquimioterapia , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Antígeno B7-H1/análisis , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Indoles/química , Indoles/farmacología , Liposomas/química , Liposomas/farmacología , Masculino , Metformina/química , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Imagen Óptica , Tamaño de la Partícula , Propiedades de Superficie , Hipoxia Tumoral/efectos de los fármacos
7.
Nat Commun ; 12(1): 736, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531508

RESUMEN

Poly-(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) are key enzymes in the DNA damage response. Four different inhibitors (PARPi) are currently in the clinic for treatment of ovarian and breast cancer. Recently, histone PARylation Factor 1 (HPF1) has been shown to play an essential role in the PARP1- and PARP2-dependent poly-(ADP-ribosylation) (PARylation) of histones, by forming a complex with both enzymes and altering their catalytic properties. Given the proximity of HPF1 to the inhibitor binding site both PARPs, we hypothesized that HPF1 may modulate the affinity of inhibitors toward PARP1 and/or PARP2. Here we demonstrate that HPF1 significantly increases the affinity for a PARP1 - DNA complex of some PARPi (i.e., olaparib), but not others (i.e., veliparib). This effect of HPF1 on the binding affinity of Olaparib also holds true for the more physiologically relevant PARP1 - nucleosome complex but does not extend to PARP2. Our results have important implications for the interpretation of PARP inhibition by current PARPi as well as for the design and analysis of the next generation of clinically relevant PARP inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Portadoras/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Proteínas Nucleares/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Benzamidas/farmacología , Bencimidazoles/farmacología , Sitios de Unión , Proteínas Portadoras/genética , Catálisis/efectos de los fármacos , Dominio Catalítico , Enzimas Reparadoras del ADN/genética , Humanos , Indazoles/farmacología , Indoles/farmacología , Proteínas Nucleares/genética , Ftalazinas/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos
8.
Molecules ; 26(2)2021 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-33419179

RESUMEN

A new conjugate of gallato zirconium (IV) phthalocyanine complexes (PcZrGallate) has been obtained from alkilamino-modified SiO2 nanocarriers (SiO2-(CH2)3-NH2NPs), which may potentially be used in photodynamic therapy of atherosclerosis. Its structure and morphology have been investigated. The photochemical properties of the composite material has been characterized. in saline environments when exposed to different light sources Reactive oxygen species (ROS) generation in DMSO suspension under near IR irradiation was evaluated. The PcZrGallate-SiO2 conjugate has been found to induce a cytotoxic effect on macrophages after IR irradiation, which did not correspond to ROS production. It was found that SiO2 as a carrier helps the photosensitizer to enter into the macrophages, a type of cells that play a key role in the development of atheroma. These properties of the novel conjugate may make it useful in the photodynamic therapy of coronary artery disease.


Asunto(s)
Complejos de Coordinación , Portadores de Fármacos , Indoles , Fotoquimioterapia , Fármacos Fotosensibilizantes , Placa Aterosclerótica , Dióxido de Silicio , Circonio , Animales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Indoles/química , Indoles/farmacología , Ratones , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Células RAW 264.7 , Dióxido de Silicio/química , Dióxido de Silicio/farmacología , Circonio/química , Circonio/farmacología
9.
Psychopharmacology (Berl) ; 238(4): 1111-1120, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33511450

RESUMEN

RATIONALE: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. METHODS: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.


Asunto(s)
Conducta Animal/efectos de los fármacos , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Receptor de Serotonina 5-HT1B/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Sustitución de Aminoácidos , Animales , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Genotipo , Hipercinesia/genética , Hipercinesia/psicología , Indoles/farmacología , Masculino , Ratones , Mutación/genética , Inhibición Prepulso/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Proteínas Proto-Oncogénicas c-fos/genética , Filtrado Sensorial/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología
10.
J Med Chem ; 64(2): 980-990, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33434430

RESUMEN

Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha activity with a small molecule (SR18292, 16) can reduce glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Despite structural similarities in 16 to known ß-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking ß-adrenergic activity that still maintain the ability to suppress glucagon-induced glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Hence, these compounds exert their biological effects in a mechanism that does not include adrenergic signaling. These probe molecules may lead to a new therapeutic approach to treat T2D either as a single agent or in combination therapy.


Asunto(s)
Glucagón/antagonistas & inhibidores , Gluconeogénesis/efectos de los fármacos , Hipoglucemiantes/farmacología , Indoles/farmacología , Propanoles/farmacología , Adipocitos Marrones/efectos de los fármacos , Adipocitos Marrones/metabolismo , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hipoglucemiantes/química , Indoles/química , Lipólisis/efectos de los fármacos , Glucógeno Hepático/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR gamma/efectos de los fármacos , Propanoles/química , Receptores Adrenérgicos beta/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Sistema Nervioso Simpático/efectos de los fármacos
11.
Psychopharmacology (Berl) ; 238(4): 1087-1098, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33442771

RESUMEN

RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS: GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.


Asunto(s)
Antipsicóticos/farmacología , Indoles/farmacología , Receptor Cannabinoide CB1/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Línea Celular , Maleato de Dizocilpina , Relación Dosis-Respuesta a Droga , Dronabinol/farmacología , Antagonistas de Aminoácidos Excitadores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Fosforilación , Inhibición Prepulso/efectos de los fármacos , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Psicosis Inducidas por Sustancias/psicología , Ratas , Ratas Long-Evans
12.
J Mater Chem B ; 9(4): 1151-1161, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33434248

RESUMEN

Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most prostate tumor cells and is considered a promising target for prostate cancer imaging and treatment. It is possible to establish a PSMA-targeted theranostic probe to achieve early diagnosis and treatment of this cancer type. In this contribution, we prepared a multifunctional melanin-like polydopamine (PDA) nanocarrier decorated with a small-molecule PSMA inhibitor, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL). PDA-DCL was then functionalized with perfluoropentane (PFP) and loaded with the photosensitizer chlorin e6 (Ce6) to give Ce6@PDA-DCL-PFP, which was successfully used for ultrasound-guided combined photodynamic/photothermal therapy (PDT/PTT) of prostate cancer. Compared with the corresponding non-targeted probe (Ce6@PDA-PEG-PFP), our targeted probe induced higher cellular uptake in vitro (6.5-fold) and more tumor accumulation in vivo (4.6-fold), suggesting strong active targeting capacity. Meanwhile, this new nanoplatform significantly enhanced the ultrasound contrast signal at the tumor site in vivo, thus facilitating precise and real-time detection of the tumor. In addition, this Ce6-loaded PDA nanoplatform produced a synergistic effect of PDT and PTT under 660 nm and 808 nm irradiation, inducing a more efficient killing effect compared with the individual therapy in vitro and in vivo. Furthermore, the tumor in the targeted group was more effectively suppressed than that in the non-targeted group under the same irradiation condition. This multifunctional probe may hold great potential for precise and early theranostics of prostate cancer.


Asunto(s)
Antineoplásicos/farmacología , Nanopartículas/química , Fármacos Fotosensibilizantes/farmacología , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/tratamiento farmacológico , Nanomedicina Teranóstica , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Fluorocarburos/química , Fluorocarburos/farmacología , Humanos , Indoles/química , Indoles/farmacología , Rayos Infrarrojos , Masculino , Tamaño de la Partícula , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Polímeros/química , Polímeros/farmacología , Porfirinas/química , Porfirinas/farmacología , Antígeno Prostático Específico/antagonistas & inhibidores , Neoplasias de la Próstata/patología , Propiedades de Superficie , Células Tumorales Cultivadas
13.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33440983

RESUMEN

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Asunto(s)
Antivirales/uso terapéutico , /terapia , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Amidas/farmacología , Amidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Cloroquina/farmacología , Cloroquina/uso terapéutico , Combinación de Medicamentos , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Inmunización Pasiva , Indoles/farmacología , Indoles/uso terapéutico , Interferones/farmacología , Interferones/uso terapéutico , Ivermectina/farmacología , Ivermectina/uso terapéutico , Lopinavir/farmacología , Lopinavir/uso terapéutico , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Purinas/farmacología , Purinas/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ribavirina/farmacología , Ribavirina/uso terapéutico , Ritonavir/farmacología , Ritonavir/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Tiazoles/farmacología , Tiazoles/uso terapéutico
14.
Eur J Pharmacol ; 894: 173836, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33387467

RESUMEN

The COVID-19 pandemic has spread rapidly and poses an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). China's prevention and treatment guidelines suggest the use of an anti-influenza drug, arbidol, for the clinical treatment of COVID-19. Reports indicate that arbidol could neutralize SARS-CoV-2. Monotherapy with arbidol is superior to lopinavir-ritonavir or favipiravir for treating COVID-19. In SARS-CoV-2 infection, arbidol acts by interfering with viral binding to host cells. However, the detailed mechanism by which arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition of SARS-CoV-2 by arbidol. Molecular dynamics (MD) simulation-based analyses demonstrate that arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with the RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between the RBD and ACE2 in the arbidol-bound RBD/ACE2 complex, suggesting that arbidol generates favorable interactions between them. Based on our MD simulation results, we propose that the binding of arbidol induces structural rigidity in the viral glycoprotein, thus restricting the conformational rearrangements associated with membrane fusion and virus entry. Furthermore, key residues of the RBD and ACE2 that interact with arbidol were identified, opening the door for developing therapeutic strategies and higher-efficacy arbidol derivatives or lead drug candidates.


Asunto(s)
Antivirales/metabolismo , Antivirales/farmacología , Indoles/metabolismo , Indoles/farmacología , /efectos de los fármacos , /metabolismo , Simulación por Computador , Glicoproteínas/efectos de los fármacos , Glicoproteínas/metabolismo , Humanos , Fusión de Membrana/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Dominios Proteicos
15.
J Cancer Res Clin Oncol ; 147(3): 767-777, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33389075

RESUMEN

PURPOSE: Approximately 60% of patients with melanoma harbor BRAF mutation and targeting BRAF offers enormous advance in the treatment of those patients. Unfortunately, the efficacy of the BRAF inhibitors is usually restricted by the onset of drug resistance. Therefore, better understanding of the adaptive drug resistance mechanisms is essential for the development of alternative therapeutic strategies, and offers more promising measures to promote the short duration of response to BRAF inhibitors. METHODS: The levels of tumor suppressive long noncoding RNA on chromosome 8p12 (TSLNC8) were evaluated by qPCR. The MTT assay, colony formation assay, apoptosis assay, and in vivo xenograft tumor model were performed to assess the functions of TSLNC8 on drug resistance. Western blotting, RNA pull-down, and RNA immunoprecipitation (RIP) assays were applied to investigate the mechanisms of TSLNC8 in melanoma. RESULTS: Herein, our findings demonstrate that TSLNC8 is significantly downregulated in BRAF inhibitor-resistant melanoma tissues and cells. Moreover, downregulation of TSLNC8 in BRAF inhibitor sensitive cells reduces the toxicity response to BRAF inhibitor PLX4720, and inhibits apoptosis of melanoma cells-treated with PLX4720. Further assay elucidates that TSLNC8 can bind with the catalytic subunit of protein phosphatase 1α (PP1α) to regulate its distribution, and Downregulation of TSLNC8 results in PP1α cytoplasmic accumulation, thus re-activating the MAPK signaling. Eventually, the overexpression of TSLNC8 in BRAF inhibitor PLX4720-resistant melanoma cells restores the sensitive to BRAF inhibitor. CONCLUSION: Collectively, our research provides a compelling rationale for resistance to BRAF inhibitor in melanoma, and the patient might benefit from the combinatorial therapy of BRAF inhibitors and lncRNA TSLNC8.


Asunto(s)
Indoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/tratamiento farmacológico , Proteína Fosfatasa 1/metabolismo , ARN Largo no Codificante/metabolismo , Sulfonamidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo , Resistencia a Antineoplásicos , Femenino , Células HEK293 , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , ARN Largo no Codificante/genética , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Nat Commun ; 12(1): 668, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510133

RESUMEN

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 µM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.


Asunto(s)
/tratamiento farmacológico , /efectos de los fármacos , /efectos de los fármacos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Antivirales/farmacología , Línea Celular , Chlorocebus aethiops , Humanos , Indoles/farmacología , Piridinas/farmacología , Células Vero , /metabolismo
17.
ACS Appl Mater Interfaces ; 13(2): 3089-3097, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33400490

RESUMEN

Numerous efforts to fabricate antimicrobial surfaces by simple yet universal protocols with high efficiency have attracted considerable interest but proved to be particularly challenging. Herein, we designed and fabricated a series of antimicrobial polymeric coatings with different functions from single to multiple mechanisms by selectively utilizing diethylene glycol diglycidyl ether (PEGDGE), polylysine, and poly[glycidylmethacrylate-co-3-(dimethyl(4-vinylbenzyl)ammonium)propyl sulfonate] (poly(GMA-co-DVBAPS)) via straightforward mussel-inspired codeposition techniques. Bactericidal polylysine endowed the modified surfaces with a high ability (∼90%) to kill attached bacteria, while PEGDGE components with unique surface hydration prevented bacterial adhesion, avoiding the initial biofilm formation. Moreover, excellent salt-responsive poly(GMA-co-DVBAPS) enabled reactant polymeric coatings to change chain conformations from shrinkable to stretchable state and subsequently release >90% attached bacteria when treated with NaCl solution, even after repeated cycles. Therefore, the obtained polymeric coatings, polydopamine/poly(GMA-co-DVBAPS) (PDA/PDV), polydopamine/polylysine/poly(GMA-co-DVBAPS) (PDA/l-PDV), and polydopamine/polylysine/poly(GMA-co-DVBAPS)/diethylene glycol diglycidyl ether (PDA/l-PDV-PEGDGE), controllably realized functions from single and dual to multiple antimicrobial mechanisms, as evidenced by long-term antifouling activity to bacteria, high bactericidal efficiency, and salt-responsive bacterial regeneration performance with several bacterial killing-release cycles. This study not only contributes to mussel-inspired chemistry for polymeric coatings with controllable functions but also provides a series of reliable and highly efficient antimicrobial surfaces for potential biomedical applications.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Polímeros/química , Polímeros/farmacología , Animales , Adhesión Bacteriana/efectos de los fármacos , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/prevención & control , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Bivalvos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/fisiología , Glicoles de Etileno/química , Glicoles de Etileno/farmacología , Humanos , Indoles/química , Indoles/farmacología , Polilisina/química , Polilisina/farmacología , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Propiedades de Superficie
18.
Biochim Biophys Acta Gen Subj ; 1865(1): 129773, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33132199

RESUMEN

BACKGROUND: Quinazolines 1 to 6, with an aromatic or aryl-vinyl substituent in position 2 are selected with the aim to compare their structures and biological activity. The selection includes a natural alkaloid, schizocommunin, and the synthetic 2-(2'-quinolyl)-3H-quinazolin-4-one, known to interact with guanine-quadruplex dependent enzymes, respectively telomerase and topoisomerase. METHODS: Breast cancer cells of the MDA cell line have been used to study the bioactivity of the tested compounds by the method of Comet Assay and FACS analyses. We model observed effects assuming stacking interactions of studied heterocycles with a naked skeleton of G-quadruplex, consisting of guanine quartet layers and potassium ions. Interaction energies are computed using a dispersion corrected density functional theory method, and an electron-correlated molecular orbital theory method. RESULTS: Selected compounds do not remarkably delay nor change the dynamics of cellular progression through the cell cycle phases, while changing significantly cell morphology. Our computational models quantify structural effects on heterocyclic G4-complex stabilization energies, which directly correlate with observed biological activity. CONCLUSION: Our computational model of G-quadruplexes is an acceptable tool for the study of interaction energies of G-quadruplexes and heterocyclic ligands, predicting, and allowing design of novel structures. GENERAL SIGNIFICANCE: Genotoxicity of quinazolin-4-one analogues on human breast cancer cells is not related to molecular metabolism but rather to their interference with G-quadruplex regulatory mechanisms. Computed stabilization energies of heterocyclic ligand complexes of G-quadruplexes might be useful in the prediction of novel telomerase / helicase, topoisomerase and NA polymerase dependent drugs.


Asunto(s)
G-Cuádruplex/efectos de los fármacos , Quinazolinas/química , Quinazolinas/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Indoles/química , Indoles/farmacología , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacología , Telómero/química
19.
Pest Manag Sci ; 77(1): 148-158, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32648658

RESUMEN

BACKGROUND: Overexpressing CIRCADIAN CLOCK ASSOCIATED1 in Arabidopsis thaliana (CCA1-ox) increases indole glucosinolate production and resistance to green peach aphid (Myzus persicae). Little is known of how aphids respond to this group of plant defense compounds or of the underlying molecular mechanism. RESULTS: Aphids reared on CCA1-ox for over 40 generations (namely the CCA population) became less susceptible to CCA1-ox than aphids maintained on the wild-type Col-0 (namely the COL population). This elevated tolerance was transgenerational as it remained for at least eight generations after the CCA population was transferred to Col-0. Intriguingly, transcriptome analysis indicated that all differential cytochrome P450 monooxygenase genes (MpCYPs), primarily MpCYP4s, MpCYP380s and MpCYP6s, were more highly expressed in the CCA population. Application of a P450 inhibitor to the CCA population resulted in decreased aphid reproduction on CCA1-ox, which was not observed if aphids were reared on Col-0. When indole glucosinolate biosynthesis in CCA1-ox was blocked using virus-induced gene silencing, the effect of the P450 inhibitor on the CCA population was attenuated, affirming the essential role played by MpCYPs in counteracting the defense mechanism in CCA1-ox that is low or absent in Col-0. Furthermore, we used host-induced gene silencing to identify MpCYP380C6 and MpCYP380C9 that specifically facilitated the CCA population to cope with CCA1-mediated plant defense. Expression profiles revealed their possible contribution to the transgenerational tolerance observed in aphids. CONCLUSION: MpCYP380C6 and MpCYP380C9 in aphids play a crucial role in mitigating indole glucosinolate-mediated plant defense, and this effect is transgenerational.


Asunto(s)
Áfidos , Prunus persica , Animales , Áfidos/genética , Sistema Enzimático del Citocromo P-450/genética , Glucosinolatos , Indoles/farmacología
20.
Methods Mol Biol ; 2225: 199-216, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33108664

RESUMEN

Necroptosis has been implicated as a critical cell death pathway in cancers, Alzheimer's and other neurodegenerative diseases, and virus-infected cells. Necroptosis occurs when mixed-lineage kinase domain-like protein (MLKL) punctures the cytoplasmic membrane allowing a rapid influx of water leading to a loss of cellular integrity. As its role in human disease becomes apparent, methods identifying necroptosis will need to be further developed and optimized. Here we describe identification of necroptosis through quantifying cell death with pathway inhibitors and using western blots to identify end points of MLKL activation and protein-protein interactions leading to it.


Asunto(s)
Fibroblastos/virología , Immunoblotting/métodos , Necroptosis/genética , Proteínas Quinasas/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Acrilamidas/farmacología , Animales , Benzotiazoles/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Colorantes Fluorescentes/química , Regulación de la Expresión Génica , Humanos , Imidazoles/farmacología , Indoles/farmacología , Necroptosis/efectos de los fármacos , Oligopéptidos/farmacología , Fosforilación/efectos de los fármacos , Proteínas Quinasas/metabolismo , Multimerización de Proteína/efectos de los fármacos , Quinolinas/farmacología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Succinimidas/química , Sulfonamidas/farmacología , Virus Vaccinia/crecimiento & desarrollo
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