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1.
Acta Pharmaceutica Sinica B ; (6): 2655-2669, 2021.
Article in English | WPRIM | ID: wpr-888878

ABSTRACT

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53

2.
Acta Pharmaceutica Sinica B ; (6): 2416-2448, 2021.
Article in English | WPRIM | ID: wpr-888868

ABSTRACT

Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.

3.
Acta Pharmaceutica Sinica B ; (6): 2396-2415, 2021.
Article in English | WPRIM | ID: wpr-888867

ABSTRACT

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of

4.
Acta Pharmaceutica Sinica B ; (6): 1446-1468, 2021.
Article in English | WPRIM | ID: wpr-888814

ABSTRACT

The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous, ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates. Because many of these clients are overexpressed or become mutated during cancer progression, Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways simultaneously. The first discovered Hsp90 inhibitors, geldanamycin and radicicol, function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity. However, most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms. Consequently, alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition, isoform-selective inhibition, and the disruption of Hsp90 protein-protein interactions. Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex, along with various co-chaperones and immunophilins, the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

5.
Article in Chinese | WPRIM | ID: wpr-906771

ABSTRACT

@#Sphingosine kinase 1 (SphK1) is an important protein that regulates the lipid microenvironment of cell membranes, and plays an important role in the dynamic equilibrium of ceramide, sphingosine and sphingosine-1-phosphate.The overexpression of SphK1 is closely related to the occurrence, development and migration of tumors as well as the generation of drug resistance.SphK1 inhibitors can induce apoptosis of various tumor cells and reverse drug resistance, which has a good prospect for drug development.In this article, the structural biology of SphK1, the structural types and structure-activity relationships of SphK1 inhibitors are reviewed.

6.
Acta Pharmaceutica Sinica B ; (6): 3015-3034, 2021.
Article in English | WPRIM | ID: wpr-922781

ABSTRACT

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERR

7.
Acta Pharmaceutica Sinica B ; (6): 1300-1314, 2021.
Article in English | WPRIM | ID: wpr-881200

ABSTRACT

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (

8.
Acta Pharmaceutica Sinica B ; (6): 810-822, 2021.
Article in English | WPRIM | ID: wpr-881170

ABSTRACT

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (

9.
Acta Pharmaceutica Sinica B ; (6): 781-794, 2021.
Article in English | WPRIM | ID: wpr-881169

ABSTRACT

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-

10.
Acta Pharmaceutica Sinica B ; (6): 488-504, 2021.
Article in English | WPRIM | ID: wpr-881149

ABSTRACT

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor

11.
Acta Pharmaceutica Sinica B ; (6): 373-393, 2021.
Article in English | WPRIM | ID: wpr-881142

ABSTRACT

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

12.
Acta Pharmaceutica Sinica B ; (6): 355-372, 2021.
Article in English | WPRIM | ID: wpr-881141

ABSTRACT

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (

13.
Acta Pharmaceutica Sinica B ; (6): 203-221, 2021.
Article in English | WPRIM | ID: wpr-881133

ABSTRACT

@#New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-lactam antibiotics, posing an emerging threat to public health. There are currently less effective treatment options for treating NDM-1 positive “superbug”, and no promising NDM-1 inhibitors were used in clinical practice. In this study, structure–activity relationship based on thiosemicarbazone derivatives was systematically characterized and their potential activities combined with meropenem (MEM) were evaluated. Compounds 19bg and 19bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance. Further studies demonstrated compounds 19bg and 19bh were uncompetitive NDM-1 inhibitors with Ki = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated that compounds 19bg and 19bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem. Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/mL against red blood cells. In vivo experimental results showed combination of MEM and compound 19bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice. Our finding showed that compound 19bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.

14.
Acta Pharmaceutica Sinica B ; (6): 156-180, 2021.
Article in English | WPRIM | ID: wpr-881131

ABSTRACT

@#This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

15.
Acta Pharmaceutica Sinica B ; (6): 13-29, 2021.
Article in English | WPRIM | ID: wpr-881122

ABSTRACT

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.

16.
Rev. cienc. med. Pinar Rio ; 25(2): e4792, 2021.
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1289118

ABSTRACT

RESUMEN Introducción: la aparición de la pandemia de la COVID-19 trajo como resultado que más de 180 países estén afectados. Cuba no ha estado ajena a esta situación. El primer evento epidemiológico registrado en la comunidad Camilo Cienfuegos, municipio Consolación del Sur, provincia Pinar del Río, que puso a prueba la capacidad de movilización del personal médico, y de los sectores que de una u otra forma colaboraron en la puesta en cuarentena entre el 31 de marzo y el 1º de mayo, para evitar la propagación. Objetivo: caracterizar el comportamiento de la comunidad Camilo Cienfuegos durante la cuarentena por la COVID-19. Métodos: se utilizaron métodos empíricos, la observación, revisión documental, entrevistas a miembros del equipo médico y a dirigentes de la comunidad. Desarrollo: se logró una caracterización de la comunidad en el proceso de la cuarentena a partir de su indicación por el Consejo de Defensa Municipal, para el enfrentamiento y la prevención del surgimiento de nuevos casos de la enfermedad. Conclusiones: la caracterización histórica de la comunidad Camilo Cienfuegos permitió al Consejo de Defensa Municipal disponer de una herramienta testimonial sobre el tratamiento de la COVID-19, lo que facilitó su aplicación o consulta a posteriores situaciones episódicas de la enfermedad en la provincia y el país. Así como su importancia para la toma de decisiones en el enfrentamiento a la pandemia.


ABSTRACT Introduction: the emergence of Covid-19 pandemic resulted in more than 180 countries being affected today. Cuba has not been exempt from this situation and its first epidemiological event took place in Camilo Cienfuegos community, Consolacion del Sur municipality, Pinar del Río province, which tested the mobilization capacity of the medical personnel, and of the sectors that in one way or another collaborated in the period of quarantine between March 31 and May 1, in order to avoid the spread and the onset of new cases. Objective: to characterize the behavior of Camilo Cienfuegos community during Covid-19 period of quarantine. Methods: empirical methods such as observation, documentary review and interviews with members of the medical team and community leaders were applied. Development: a characterization of the community in the quarantine process was accomplished complying with the indications of the Municipal Defense Council to cope with and prevent the onset of Covid-19 new cases. Conclusions: the historical characterization of Camilo Cienfuegos community allowed the Municipal Defense Council to have a testimonial tool on the treatment of Covid-19, which facilitated the further requests or enquiries of posterior episodic situations of this disease in the province and the country, as well as its importance for decision making in coping with this pandemic.

17.
Mem. Inst. Oswaldo Cruz ; 116: e210127, 2021. tab
Article in English | LILACS-Express | LILACS | ID: biblio-1356486

ABSTRACT

The process of adaptation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to humans probably had started decades ago, when its ancestor diverged from the bat coronavirus. The adaptive process comprises strategies the virus uses to overcome the respiratory tract defense barriers and replicate and shed in the host cells. These strategies include the impairment of interferon production, hiding immunogenic motifs, avoiding viral RNA detection, manipulating cell autophagy, triggering host cell death, inducing lymphocyte exhaustion and depletion, and finally, mutation and escape from immunity. In addition, SARS-CoV-2 employs strategies to take advantage of host cell resources for its benefits, such as inhibiting the ubiquitin-proteasome system, hijacking mitochondria functions, and usage of enhancing antibodies. It may be anticipated that as the tradeoffs of adaptation progress, the virus destructive burden will gradually subside. Some evidence suggests that SARS-CoV-2 will become part of the human respiratory virome, as had occurred with other coronaviruses, and coevolve with its host.

18.
Medisan ; 24(4)jul.-ago. 2020.
Article in Spanish | LILACS, CUMED | ID: biblio-1125141

ABSTRACT

Se describe el caso clínico de un adolescente de 18 años de edad con antecedentes patológicos personales de hipertensión arterial crónica esencial y obesidad de grado II, que fue atendido en el Hospital Pediátrico Provincial José Martí Pérez de Sancti Spíritus por presentar tos húmeda ocasional, fiebre y falta de aire. Inicialmente se diagnosticó neumonía en la base del pulmón derecho, que luego evolucionó a bronconeumonía. Durante su hospitalización se recibió el resultado de la prueba de reacción en cadena de la polimerasa en tiempo real, que fue positivo en el coronavirus SARS-CoV-2. Se logró estabilizar el cuadro clínico del paciente, el cual tuvo una evolución favorable; se le dio el alta hospitalaria tras cumplir el periodo de vigilancia epidemiológica.


The case report of an 18 years teenager with a personal pathological history of chronic essencial hypertension and grade II obesity, who was assisted in José Martí Provincial Pediatric Hospital from Sancti Spiritus due to occasional humid cough, fever and lack of air. Initially pneumonia was diagnosed at the base of the right lung, which became a bronchopneumonia later. During his hospitalization, the result of the polymerase reaction test in real time was received, which was positive in the coronavirus SARS-CoV-2. It was possible to stabilize the patient clinical pattern, which had a favorable clinical course; he was discharged after fulfilling the surveillance period.


Subject(s)
Bronchopneumonia , Coronavirus Infections , Betacoronavirus , Adolescent , Hypertension , Obesity
19.
Rev. cuba. oftalmol ; 33(2): e943,
Article in Spanish | LILACS, CUMED | ID: biblio-1139077

ABSTRACT

RESUMEN La Organización Mundial de la Salud declaró el 11 de marzo del año 2020 pandemia por la COVID-19, enfermedad causada por el SAR-COV-2. Al no existir medicamentos efectivos disponibles para esta infección viral, muchos han sido los esfuerzos de las políticas de salud para lograr un control adecuado de la fuente de infección, la transmisión y la protección en poblaciones susceptible, mediante las cuarentenas obligatorias como medida oportuna de prevención. Hasta el momento la presencia de conjuntivitis viral y el riesgo de contagio por vía ocular son datos mencionados en la literatura internacional en el curso de diversas investigaciones. Se conoce que el virus puede aislarse en la lágrima y en la conjuntiva, y que su transmisibilidad por las secreciones oculares es posible. La actual pandemia del coronavirus es una emergencia sanitaria mundial y muchos países han sido actualmente afectados con miles de fallecidos. Se realizó una búsqueda de diversos artículos publicados, con el objetivo de conocer las manifestaciones oculares de la COVID-19 reportadas por diferentes investigadores. Se utilizó la plataforma Infomed, específicamente la Biblioteca Virtual de Salud(AU)


ABSTRACT COVID-19, a disease caused by SARS-CoV-2, was declared pandemic by the World Health Organization on 11 March 2020. In the absence of effective medications for this viral infection, many have been the efforts made by health policies to adequately control the source of infection and transmission, and to protect susceptible populations through compulsory quarantine as a timely prevention measure. Viral conjunctivitis and risk of contagion via the ocular route have been mentioned in a variety of international studies contained in the bibliography about the topic. It has been found that the virus may be isolated from tears and from the conjunctiva, and that it may be transmitted via ocular secretion. The current coronavirus pandemic is a world health emergency causing thousands of deaths in many countries. A search was conducted for published papers to identify the ocular manifestations of COVID-19 reported by researchers. Use was made of the platform Infomed, specifically the Virtual Health Library(AU)


Subject(s)
Humans , Conjunctivitis, Viral , Coronavirus Infections/epidemiology , Eye Diseases/etiology , Review Literature as Topic
20.
Rev. colomb. cienc. pecu ; 33(1): 32-43, Jan.-Mar. 2020. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1156301

ABSTRACT

Abstract Background: Shrimp farming is evolving from semi-intensive to hyper-intensive systems with biofloc technology and water recirculation systems. Objective: To evaluate the transcriptional response promoted by biofloc on shrimp (Litopenaeus vannamei) under a recirculating aquaculture system (RAS). Methods: Quantitative real-time RT-PCR was used to monitor seven key genes related to the immune system in shrimp post-larvae, reared in a RAS with and without biofloc (BF and no- BF). In addition, we present for the first time nucleotide sequences of ADP-ribosylation factor 4 (LvArf4) from Litopenaeus vannamei. Results: Transcripts for penaeidin3 (Pen3), penaeidin4 (Pen4), crustin, and Toll receptor (LvToll) genes were up-regulated between 3 and 24 h in both systems, and tumor necrosis factor receptor-associated factor 6 (TRAF6) in no-BF as an early response. Regarding differential expression between treatments, 13 occurrences were encountered. Nine that were higher in BF than in no-BF and four higher in no-BF than in BF. In some sample times, expression of Pen3, crustin, LvToll, TRAF6, IMD, and LvArf4 was higher in BF than in no-BF and in others, expression of Pen3, Pen4, and TRAF6 was higher in no-BF than in BF. Conclusions: BF modulates the transcription of genes related to the immune response in shrimp as an early response. However, the RAS with no-BF promotes a similar response.


Resumen Antecedentes: Los cultivos de camarón están evolucionando de sistemas semi-intensivos a hiper-intensivos con biofloc y con recirculación. Objetivo: Evaluar la respuesta transcripcional promovida por el biofloc en un sistema acuícola con recirculación (SAR). Métodos: Monitoreamos mediante RT-PCR cuantitativo siete genes relacionados con el sistema inmune en postlarvas de camarón cultivadas en un SAR con y sin biofloc (BF y no-BF). Además, presentamos por primera vez la secuencia de nucleótidos del factor de ribosilación 4 de ADP (LvArf4) de Litopenaeus vannamei. Resultados: Los genes penaeidina3 (Pen3), penaeidina4 (Pen4), Crustina y Toll (LvToll) se sobre-expresaron entre las 3 y 24 h en ambos sistemas, y el factor 6 asociado al factor de necrosis tumoral (TRAF6) en BF como una respuesta temprana. Con respecto a la expresión diferencial entre los tratamientos, se presentaron 13 ocurrencias. Nueve donde el BF fue mayor que sin-BF y cuatro donde el no-BF fue mayor que el BF. La expresión fue más alta en BF que en no-BF en Pen3, Crustin, LvToll, TRAF6, IMD y LvArf4. En contraste, la expresión fue mayor en no-BF en Pen3, Pen4 y TRAF6. Conclusión: el BF modula la transcripción de los genes relacionados con la respuesta inmune en camarón como una respuesta temprana. Sin embargo, el SAR sin-BF promueve una respuesta similar.


Resumo Antecedentes: A criação de camarões está evoluindo de sistemas semi-intensivos para hiper-intensivos como tecnologia de bioflocos e sistemas de recirculação. Objetivo: Avaliar a resposta transcricional promovida pelo biofloco em um sistema de aquicultura recirculante (SAR). Métodos: Utilizamos RT-PCR quantitativo em tempo real para monitorar sete genes-chave relacionados ao sistema imune em pós-larvas de camarão, criados em SAR com e sem bioflocos (BF e no-BF). Além disso, apresentamos pela primeira vez sequências nucleotídicas do fator de ribosilação do ADP 4 (LvArf4) de Litopenaeus vannamei. Resultados: Os resultados mostraram que o Penaeidina3 (PEN3), Penaeidina4 (Pen4), Crustina e Toll genes (LvToll) foram sobre-expressos entre 3 e 24 h em ambos os sistemas, e o Factor de Necrose do Receptor 6 associado e protuberância (TRAF6) no BF como uma resposta precoce. Com relação à expressão diferencial entre tratamentos, 13 ocorrências foram apresentadas. Nove onde o BF foi maior do que os não-BF e quatro onde o não-BF foi maior do que o BF. A expressão foi maior do que em BF não-BF em Pen3, Crustin, LvToll, TRAF6, IMD e LvArf4. Em contraste, a expressão foi mais elevada no não-BF em Pen3, Pen4 e TRAF6. Conclusões: O BF modula a transcrição de resposta imune relacionada no camarão como um genes de resposta precoce. No entanto, o SAR não BF promove uma resposta semelhante.

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